Abstract
Background
Liver transplantation (LT) is an accepted therapeutic option for hepatocellular carcinoma (HCC) in patients with cirrhosis. Despite careful candidate selection, HCC recurrence occurs. We aimed to describe the predictors of recurrence, clinical presentation, and predictors of survival after HCC recurrence post-LT.
Methods
Patients with recurrent HCC after LT between January 1996 and December 2017 were retrospectively reviewed.
Results
Of 711 patients, 96 (13.5%) patients had post-LT HCC recurrence. The median time to recurrence was 17.1 months, and the median survival was 10.1 months. Initial recurrence was more often in the graft (34.4%), and most (60.4%) had multiple recurrent lesions, and 26% were in multiple sites. In multivariate analysis, factors associated with shorter survival were poorly differentiated histology in explant (Hazard ratio [HR] = 1.96; p = 0.027), bilirubin ≥1.2 mg/dL (HR = 2.47; p = 0.025), and albumin <3.5 mg/dL (HR = 2.13; p = 0.014) at recurrence, alpha-fetoprotein at recurrence ≥ 1000 ng/mL (HR = 2.96; p = 0.005), and peritoneal disease (HR = 3.20; p = 0.022). There was an increased survival in patients exposed to sirolimus (HR = 0.32; p < 0.0001).
Conclusions
Recurrent HCC after LT is often in extrahepatic sites with a decreased survival in those with poorly differentiated explant pathology, high bilirubin, low albumin, marked elevation of alpha-fetoprotein at recurrence, and peritoneal recurrence. Sirolimus-based immunosuppression may provide benefit.
Keywords: liver transplantation, hepatocellular carcinoma, recurrence, survival, immunosuppression
Abbreviations: AFP, alpha-fetoprotein; ALP, alkaline phosphatase; ALT, alanine transaminase; CNI, calcineurin inhibitor; CT, computed tomography; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; INR, international normalized ratio; LT, Liver transplantation; MRI, magnetic resonance imaging; mTOR, mammalian target of rapamycin; NASH, nonalcoholic steatohepatitis; RETREAT, Risk Estimation of Tumor Recurrence After Transplant; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; UCSF, University of California San Francisco; UNOS, United Network for Organ Sharing
Globally, the incidence of hepatocellular carcinoma (HCC) is currently increasing, and it is ranked as the third leading cause of cancer-related death1. Liver transplantation (LT) is a viable therapeutic modality for HCC in patients with cirrhosis in select cases, with ideal tumor burden criteria of single tumor ≤ 5 cm or ≤ 3 tumors with each diameter ≤ 3 cm (Milan criteria).2 In such cases that undergo LT, the overall five-year survival rate has been of 75% with a recurrence-free survival of 83% and similar to post-LT outcomes in non-HCC patients.2,3 Yet, HCC recurs after LT, and recurrence rates in post-LT period have been around 10–20%, despite careful selection of candidates.4, 5, 6 Most studies, primarily from outside of the US, have observed that HCC recurrence after LT limits survival while therapeutic options have been variable7,8. Prognosis of patients with HCC recurrence after LT is poor due to a tendency to manifest at extrahepatic metastasis6. A meta-analysis to identify pre-LT risk factors for recurrence noted that the presence of micro/macrovascular invasion, poor differentiation of tumor, tumor size > 5 cm, and tumor stage beyond the Milan criteria in the explant correlated with HCC recurrence post-LT9; additionally, the pretransplant alpha-fetoprotein (AFP) level prior to transplantation also has influenced recurrence risk and survival.7 The median time to post-LT recurrence has been noted to be around 17 months, and median survival from recurrence to be 19 months, with a three-year post recurrence survival of 26%.10 Median survival postrecurrence has been 65 months in cases of tumor amenable to surgical therapy, and five months in those unsuitable for surgical intervention(11).
Treatment of recurrent HCC in the post-LT setting can be challenging. For example, immunosuppressive agents may have effects on the wound healing process and can cause drug–drug interactions, and post-LT delicate arterial vascular anastomosis can present challenges for transarterial chemoembolization (TACE).8 Given the heterogeneity in recurrence rates, the presentation, treatment modalities applied, and the outcomes, we set out to study the clinical presentation, disease characteristics, predictors for HCC recurrence, and survival after HCC recurrence in LT recipients, in a large US single center.
Materials and methods
We retrospectively reviewed the medical records of patients who underwent LT for HCC between January 1, 1996 and December 31, 2017. The liver transplant database at the University of Pennsylvania was used to identify patients who had liver transplant during the study period. Inclusion criteria for analysis were adult patients of age ≥18 years old who underwent LT and were diagnosed with HCC and then had post-transplant recurrence. Patients with a preoperative diagnosis of HCC as well as patients with incidental HCC on explant were included in the analysis. Patients who were found to have a different tumor histology on explant (such as cholangiocarcinoma) were excluded, while those with a diagnosis of hepato-cholangiocarcinoma were included. Data collection variables included demographic information, explant pathology, laboratory tests at the time of recurrence, highest AFP levels pretransplant/AFP at the time of recurrence/highest AFP levels in post-transplant period, site and number of lesions at the time of recurrence, as well as initial treatment modalities for recurrent HCC. The study protocol was approved by the Institutional Review Board of the University of Pennsylvania.
Diagnosis, Treatment, and Follow-up of Recurrent HCC
All patients who receive a liver transplant in our institution are followed longitudinally in the liver transplant clinic. Patients with a diagnosis of HCC confirmed by explant pathology are enrolled in a surveillance protocol after LT that includes contrast-enhanced cross-sectional imaging of the chest and abdomen every six months for three years and every year for another two years (total duration of imaging surveillance of five years). Laboratory testing for AFP is performed every three months during the surveillance period.
Based on clinical practice during 1996–2008, patients with high risk HCC on explant (beyond Milan criteria, microvascular invasion, macrovascular invasion, poorly differentiated tumors) were counseled by a medical oncologist on the risks and benefits of receiving adjuvant systemic chemotherapy (doxorubicin/cisplatin/5 fluorouracil/leucovorin) after LT.
Recurrent HCC was diagnosed either from a biopsy of a lesion and/or by imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) features consistent with HCC recurrence. Decision on the management of recurrent HCC was made by consensus based on a discussion at a multidisciplinary liver tumor conference including hepatologists, transplant and hepatobiliary surgeons, pathologists, medical oncologists, interventional radiologists, and radiation oncologists. Treatment of recurrent HCC involved multimodality treatment strategies, including tumor resection, radiofrequency ablation (RFA), TACE, external radiation, systemic therapy, and supportive care.
Statistical Analysis
Our primary intention was to describe the clinical presentation and disease characteristics of recurrent HCC post-LT. The secondary outcomes included predictors of HCC recurrence and predictors of survival in recurrent HCC after LT. Demographic data and baseline characteristics were summarized using descriptive statistics such as mean ± standard deviation (SD), median (interquartile range, [IQR]), and percentage (%). The associations between individual clinical variables and HCC recurrence were tested using logistic regression. Multivariate logistic regression models were performed by including the variables significant at nominal p < 0.05 in the initial univariate logistic regression analyses. All P values represent the results of two-sided tests. P < 0.05 was considered statistically significant.
Survival was estimated by using the Kaplan–Meier method. The log-rank test was used for comparison of survival curves. The Cox proportional-hazards method was used to identify predictors of survival after HCC recurrence post-LT in multivariate analysis. Factors identified as significant (p < 0.05) on univariate analysis were entered into a multivariate Cox regression model to identify significant independent predictors of survival after HCC recurrence. Statistical analysis was performed using R 3.4.1 program (The R Foundation).
Results
A total of 711 patients with HCC who had undergone for LT between January 1996 and December 2017 at the LT center at the Hospital University of Pennsylvania were included.
Predictors of HCC Recurrence After LT
Table 1 compares the characteristics of patients with and without recurrence. In univariate analysis, factors associated with HCC recurrence after LT were peak levels of pre- and post-transplant AFP, high-risk features on explant pathology such as poorly differentiated histology, micro/macrovascular invasions, beyond Milan/University of California San Francisco (UCSF) criteria, number of lesions on the explant, maximum size and sum of tumor size on the explant, hepato-cholangiocarcinoma, and no sirolimus exposure (Table 1).
Table 1.
Baseline Characteristics of Patients With Recurrent HCC Versus No Recurrence After LT.
| Patients | No recurrence N = 615 | Recurrence N = 96 | P value |
|---|---|---|---|
| Male/Female, no (% Male) | 502/113 (81.6) | 82/14 (85.4) | 0.58 |
| Ethnicity, no (%) | 0.25 | ||
| Caucasian | 393 (63.9) | 70 (72.9) | |
| African American | 129 (20.9) | 13 (13.5) | |
| Asian | 48 (7.8) | 5 (5.2) | |
| Others | 45 (7.3) | 8 (8.3) | |
| Etiology of liver disease, no (%) | 0.86 | ||
| HCV | 436 (70.9) | 68 (70.8) | |
| Alcohol | 49 (7.9) | 9 (9.4) | |
| HBV | 44 (7.2) | 6 (6.3) | |
| NASH | 46 (7.5) | 5 (5.2) | |
| Other etiology | 40 (6.5) | 8 (8.3) | |
| AFP pretransplant peak in ng/mL, median (IQR) | 15 (6–54) | 33 (13.5–369.0) | <0.0001* |
| Pretransplant peak AFP ≥ 1000 ng/dL, no (%) | 14 (2.3) | 8 (8.3) | 0.001* |
| Explant pathology, no (%) | |||
| Poorly differentiated | 72 (11.7) | 28 (29.2) | <0.0001* |
| Microvascular invasion | 277 (45.0) | 74 (77.1) | <0.0001* |
| Macrovascular invasion | 3 (0.4) | 11 (11.5) | <0.0001* |
| Within Milan criteria | 449/148 (73/24) | 30/66 (31/68) | <0.0001* |
| Within UCSF/beyond criteria | 500/97 (81.3/15.7) | 44/52 (45.8/54.2) | <0.0001* |
| Number of lesions on explant, median (IQR) | 1.5 (1–3) | 2 (1.0–4.8) | <0.0001* |
| Maximum size of tumor on explant (mm), median (IQR) | 22 (16–31) | 38 (30.0–47.5) | <0.0001* |
| Sum of tumor size on explant (mm), median (IQR) | 32 (20–50) | 48 (40.0–83.5) | <0.0001* |
| Hepatocholangiocarcinoma | 16 (2.6) | 7 (7.3) | 0.035* |
| Immunosuppression regimena | |||
| Before recurrent HCC: Sirolimus/CNI and other (% Sirolimus) | 105/510 (17.1) | 3/93 (3.1) | <0.0001* |
| AFP post-transplant peak in ng/mL, median (IQR) | 3 (2–7) | 290 (10.8–4280.5) | <0.0001* |
| Post-transplant peak AFP ≥ 1000 ng/dL, no (%) | 0 (0) | 32 (33.3) | <0.0001* |
HCC, hepatocellular carcinoma; IQR, interquartile range; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; AFP, alpha-fetoprotein; UCSF, University of California San Francisco; mm, millimeters; CNI, calcineurin inhibitor. * P-value < 0.05.
Any sirolimus use was captured. 497/510 were on CNI-based (tacrolimus-based) immunosuppression and other 13 were on non-CNI-based immunosuppression.
In multivariate analysis, significant predictors of HCC recurrence after LT were microvascular invasion, number of lesions on the explant, maximum size of tumor on the explant, and peak levels of post-transplant AFP. Factors that were found to be significantly associated with lower rate of HCC recurrence after LT were explant pathology within Milan criteria and sirolimus exposure (Table 2).
Table 2.
Multivariate Analysis on Significant Predictors for HCC Recurrence.
| Parameter | Odd Ratio (95% CI) | P value |
|---|---|---|
| AFP pretransplant peak | 1.00 (1.00–1.00) | 0.62 |
| Poorly differentiated histology on explant (Yes/No) | 1.34 (0.85–2.12) | 0.21 |
| Microvascular invasion on explant (Yes/No) | 1.85 (1.17–2.93) | 0.008* |
| Macrovascular invasion on explant (Yes/No) | 1.54 (0.54–4.40) | 0.42 |
| Explant pathology within Milan criteria (Yes/No) | 0.55 (0.31–0.96) | 0.04* |
| Explant pathology within UCSF criteria (Yes/No) | 0.93 (0.52–1.66) | 0.8 |
| Number of lesions on explant | 1.17 (1.01–1.34) | 0.03* |
| Maximum size of tumor on explant | 1.06 (1.03–1.09) | 0.0004* |
| Sum of tumor size on explant | 0.97 (0.95–1.00) | 0.02* |
| Hepatocholangiocarcinoma (Yes/No) | 1.62 (0.80–3.28) | 0.18 |
| AFP post-transplant peak | 1.01 (1.01–1.02) | <0.0001* |
| Sirolimus exposure (Yes/No) | 0.37 (0.17–0.83) | 0.016* |
HCC, Hepatocellular carcinoma; CI, confidence interval; AFP, alpha-fetoprotein; UCSF, University of California San Francisco.
* P-value < 0.05.
There were 96 adult patients (13.5%) with recurrent HCC after LT. Seven patients (7.3%) had evidence of a combined hepato-cholangiocarcinoma in the explant liver pathology. The median time to recurrence was 17.1 (IQR 8.7–31.7) months after LT. Pathological confirmation of HCC recurrence was obtained in 68 patients (70.8%). Baseline characteristics of patients with recurrent HCC after LT are summarized in Table 3.
Table 3.
Baseline Characteristics of 96 Patients With Recurrent HCC After LT.
| Patients | 96 |
|---|---|
| Male/Female, no. (% Male) | 82/14 (85.4) |
| Ethnicity, no. (%) | |
| Caucasian/African American/Asian/Others | 70/13/5/8 (72.9/13.5/5.2/8.3) |
| Age at recurrence, median (IQR) | 59.5 (55.6–64.2) |
| Etiology of liver disease, no. (%) | |
| HCV/Alcohol/HBV/NASH/Other etiology | 68/9/6/5/8 (70.8/9.4/6.3/5.2/8.3) |
| AFP pretransplant peak in ng/mL, median (IQR) | 33 (13.5–369.0) |
| Pretransplant peak AFP ≥ 1000 ng/dL, no. (%) | 8 (8.3) |
| Explant pathology, no. (%) | |
| Incidental HCC | 10 (10.4) |
| - Poorly differentiated | 3 (3.1) |
| - Microvascular invasion | 9 (9.4) |
| - Macrovascular invasion | 1 (1.0) |
| - Within Milan criteria | 4 (4.2) |
| - Within UCSF/beyond criteria | 6/4 (6.3/4.2) |
| - Number of lesions on explant, median (IQR) | 2 (1.75–8) |
| - Maximum size of tumor on explant (mm), median (IQR) | 25 (16.5–33.75) |
| - Sum of tumor size on explant (mm), median (IQR) | 42.5 (21.75–53.25) |
| - Hepatocholangiocarcinoma | 0 (0) |
| Poorly differentiated | 28 (29.2) |
| Microvascular invasion | 74 (77.1) |
| Macrovascular invasion | 11 (11.5) |
| Within Milan criteria | 30 (31.3) |
| Within UCSF/beyond criteria | 44/52 (45.8/54.2) |
| Number of lesions on explant, median (IQR) | 2 (1.0–4.8) |
| Maximum size of tumor on explant (mm), median (IQR) | 38 (30.0–47.5) |
| Sum of tumor size on explant (mm), median (IQR) | 48 (40.0–83.5) |
| Hepatocholangiocarcinoma | 7 (7.3) |
| Adjuvant chemotherapy administered, no. (%) | |
| Yes | 29 (30.2) |
| No | 67 (69.8) |
| Time to recurrence in months, median (IQR) | 17.1 (8.7–31.7) |
| Laboratory tests at the time of recurrence, median (IQR) | |
| ALT in IU/mL | 42.0 (21.8–71.3) |
| ALP in IU/mL | 107.0 (80.5–163.8) |
| Bilirubin in mg/dL | 0.6 (0.4–0.9) |
| Albumin in mg/dL | 3.9 (3.5–4.2) |
| Creatinine in mg/dL | 1.2 (1.0–1.7) |
| INR | 1.0 (1.0–1.1) |
| AFP in ng/mL | 11.5 (3.0–128.8) |
| AFP ≥ 1000 ng/mL, no. (%) | 12 (12.5) |
| Immunosuppression regimen | |
| Before recurrent HCC: Sirolimus/CNI (% Sirolimus) | 3/93 (3.1) |
| After recurrent HCC: Sirolimus/CNI (% Sirolimus) | 54/42 (56.3) |
| AFP post-transplant peak in ng/mL, median (IQR) | 290 (10.8–4280.5) |
| Post-transplant peak AFP ≥ 1000 ng/dL, no. (%) | 32 (33.3) |
| Number of lesions at recurrence, no. (%) | |
| Single | 38 (39.6) |
| Multiple | 58 (60.4) |
| Site of initial recurrence, no. (%) | |
| Graft | 33 (34.4) |
| Lung | 32 (33.3) |
| Abdominal lymph nodes | 26 (27.1) |
| Adrenal gland | 14 (14.6) |
| Bone | 11 (11.5) |
| Peritoneum | 7 (7.3) |
| Pleura | 4 (4.2) |
| Abdominal wall | 3 (3.1) |
| Multiple sites | 25 (26.0) |
| Initial treatment of recurrent HCC, no. (%) | |
| Surgical resection | 26 (27.1) |
| Percutaneous ablation (e.g., RFA) | 5 (5.2) |
| Transarterial chemoembolization (TACE) | 1 (1.0) |
| External radiation | 10 (10.4) |
| Systemic therapy | 38 (39.6) |
| Supportive care | 16 (16.7) |
HCC, hepatocellular carcinoma; IQR, interquartile range; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; AFP, alpha-fetoprotein; UCSF, University of California San Francisco; mm, millimeters; CNI, calcineurin inhibitor; RFA, radiofrequency ablation.
The majority of patients were Caucasian 70/96 (72.9%) and male 82/96 (85.4%), with a mean age at recurrence of 59.5 (IQR 55.6–64.2) years. The etiology of pretransplant cirrhosis and liver failure was mostly hepatitis C: 68/96 (70.8%), followed by alcohol: 9/96 (9.4%), hepatitis B: 6/96 (6.3%), nonalcoholic steatohepatitis (NASH): 5/96 (5.2%), and others 8/96 (8.3%). The median peak pretransplant AFP was 33 (IQR 13.5–369.0) ng/mL; eight patients (8.3%) had at least one AFP ≥ 1000 ng/mL prior to transplant.
Most patients 67/96 (69.8%) had tumor burden within Milan criteria based on pretransplant imaging; 74/96 (77.1%) had a tumor within UCSF criteria. Ten patients (10.4%) had incidental HCC and thus had no radiologic identification of mass lesions on pretransplant radiologic studies. Within the incidental HCC patients, 9/96 (9.4%) had microvascular invasion, 1/96 patients (1.0%) had macrovascular invasion (not radiologically noted pretransplant), and 3/96 patients (3.1%) had poorly differentiated tumor. Tumor burden of incidental HCC on explant pathology was noted within Milan criteria in four patients (4.2%) and within UCSF criteria in six patients (6.3%). On explant pathology, the majority of patients, 74/96 (77.1%) had microvascular invasion, 11/96 patients (11.5%) had macrovascular invasion (not suspected or noted in pretransplant imaging studies), and 28/96 patients (29.2%) had poorly differentiated tumor. Tumor burden on explant pathology was noted to be beyond Milan criteria in 66 patients (68.8%) and beyond UCSF criteria in 52 patients (54.2%). Between 1996 and 2008, adjuvant chemotherapy was administered in 29 patients (30.2%).
At the time of recurrent HCC, 75 patients (78.1%) presented with evidence of tumor outside the liver. Majority of recurrent HCC occurred in the graft (34.4%) and lung (33.3%) were the most common metastatic sites; other metastatic sites were abdominal lymph nodes (27.1%), adrenal glands (14.6%), bone (11.5%), peritoneum (7.3%), pleura (4.2%), and abdominal wall (3.1%). Most of the patients (60.4%) had multiple lesions at recurrence, and multiple sites of recurrence were found on initial evaluation in around 26.0%. The median AFP at the time of recurrence was 11.5 (IQR 3.0–128.8) ng/mL; 12 patients (12.5%) had AFP ≥ 1000 ng/mL. Prior to recurrence, 3.1% of patients were on sirolimus-based immunosuppression, and 96.9% were on calcineurin inhibitor-based (CNI-based) immunosuppression. After recurrence, 56.3% were switched to sirolimus-based immunosuppression.
Initial treatment of recurrent HCC was surgical resection in 26 patients (27.1%), percutaneous ablation in five patients (5.2%), TACE in one patient (1.0%), external radiation in 10 patients (10.4%), and systemic therapy in 38 patients (39.6%). Further, 16 patients (16.7%) had supportive care without HCC-directed treatment. Among the 38 patients who had systemic therapy as the initial treatment, 16 patients had oxaliplatin or cisplatin-based combination chemotherapy, and 22 patients had sorafenib/other targeted therapy. A description of the treatment by location of recurrent HCC is detailed in Table 4. The overall median survival after HCC recurrence was 10.1 months (95% confidence interval [CI] of 6.5–15.7 months) (Figure 1).
Table 4.
Treatment of Recurrent HCC by Location of Recurrence.
| Initial site(s) of recurrence |
Initial treatment of recurrent HCC |
Total |
|||||
|---|---|---|---|---|---|---|---|
| Resection | Ablation | TACE | External radiation | Systemic therapy | Supportive | ||
| A | 8 | 0 | 0 | 1 | 0 | 0 | 9 |
| A, B, G | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| A, B, P, N | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| AW | 2 | 0 | 0 | 0 | 1 | 0 | 3 |
| B | 1 | 0 | 0 | 3 | 0 | 1 | 5 |
| G | 3 | 5 | 1 | 1 | 5 | 4 | 19 |
| G, A | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| G, L | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| G, N | 0 | 0 | 0 | 0 | 3 | 1 | 4 |
| G, B, N | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| G, L, P | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| G, L, N | 0 | 0 | 0 | 0 | 3 | 1 | 4 |
| L | 6 | 0 | 0 | 0 | 11 | 1 | 18 |
| L, A | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| L, B | 1 | 0 | 0 | 1 | 0 | 0 | 2 |
| L, N | 0 | 0 | 0 | 0 | 2 | 0 | 2 |
| L, PL | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| L, PL, A | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| L, G, P, N | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| N | 2 | 0 | 0 | 4 | 4 | 2 | 12 |
| P | 0 | 0 | 0 | 0 | 1 | 1 | 2 |
| P, B | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| P, N | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| PL | 2 | 0 | 0 | 0 | 0 | 0 | 2 |
| NA | 0 | 0 | 0 | 0 | 1 | 1 | 2 |
| Total | 26 | 5 | 1 | 10 | 38 | 16 | 96 |
A, adrenal; AW, abdominal wall; B, bone; G, graft; L, lung; N, abdominal lymph node; P, peritoneum; PL, pleura; TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma; NA, not available.
Figure 1.
Survival after recurrence of hepatocellular carcinoma post-LT. (Note: The shaded area represents 95% CI.)
Predictors of Survival After HCC Recurrence Post-LT
In univariate analysis, factors associated with reduced survival after recurrence were poorly differentiated histology on the explant, time to recurrence <12 months, bilirubin ≥1.2 mg/dL at time of recurrence, albumin <3.5 mg/dL at recurrence, AFP at recurrence ≥1000 ng/mL, no sirolimus exposure, graft recurrence, peritoneal recurrence, presence of multiple lesions and multiple sites of recurrence, treatment modalities and the Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score ≥ 5 (Table 5).
Table 5.
Factors Associated With Survival After Recurrent HCC Post-LT.
| Parameter | Median survival (95% CI), months | P- value |
|---|---|---|
| Female | 5.07 (2.13–16.60) | 0.15 |
| Male | 12.97 (7.70–15.70) | |
| Caucasian | 9.10 (5.93–16.30) | 0.62 |
| Non-Caucasian | 12.80 (4.67–15.50) | |
| Age < 60 years | 6.43 (5.37–13.40) | 0.35 |
| ≥60 years | 13.97 (7.73–25.40) | |
| HCV | 8.23 (5.40–15.70) | 0.52 |
| Non-HCV | 13.68 (7.73–27.60) | |
| Peak pre-LT AFP < 1000 ng/mL | 12.77 (6.43–15.70) | 0.11 |
| ≥1000 ng/mL | 7.13 (1.07 –) | |
| Incidental HCC | 7.98 (1.57–30.30) | 0.81 |
| Nonincidental HCC | 11.10 (6.07–15.50) | |
| Poorly differentiated histology on the explant | 6.50 (4.67–11.10) | 0.02* |
| Well or Moderately differentiated | 13.90 (5.93–20.90) | |
| Microvascular invasion on the explant | 10.10 (6.43–14.70) | 0.09 |
| No microvascular invasion | 11.30 (3.37–77.70) | |
| Macrovascular invasion on the explant | 5.37 (1.07–16.30) | 0.18 |
| No macrovascular invasion | 12.97 (6.50–15.70) | |
| Explant within Milan criteria | 16.25 (4.97–27.40) | 0.18 |
| Beyond criteria | 8.63 (5.93–14.00) | |
| The explant within UCSF criteria | 10.10 (4.97–24.30) | 0.40 |
| Beyond criteria | 9.10 (5.93–14.30) | |
| Adjuvant chemotherapy | 8.23 (4.73–14.00) | 0.06 |
| No adjuvant chemotherapy | 12.97 (5.93–22.70) | |
| Time to recurrence < 12 months | 5.42 (3.67–8.00) | 0.0002* |
| ≥12 months | 14.67 (8.90–26.90) | |
| ALT at recurrence < 50 IU/mL | 10.10 (6.07–14.30) | 0.87 |
| ≥50 IU/mL | 10.90 (5.37–16.60) | |
| ALP at recurrence < 130 IU/mL | 13.50 (8.90–20.90) | 0.08 |
| ≥130 IU/mL | 5.40 (4.73–8.23) | |
| Bilirubin at recurrence < 1.2 mg/dL | 13.53 (7.70–16.60) | 0.0005* |
| ≥1.2 mg/dL | 5.37 (1.83–8.23) | |
| Creatinine at recurrence < 1.2 mg/dL | 8.00 (4.73–14.30) | 0.39 |
| ≥1.2 mg/dL | 13.80 (6.43–17.30) | |
| Albumin at recurrence < 3.5 mg/dL | 5.17 (3.07–7.73) | 0.002* |
| ≥3.5 mg/dL | 13.83 (8.63–20.90) | |
| AFP at recurrence < 1000 ng/mL | 13.83 (8.23–16.60) | <0.0001* |
| ≥1000 ng/mL | 3.42 (0.57–5.63) | |
| Sirolimus exposure | 15.70 (12.77–27.40) | <0.0001* |
| No sirolimus | 5.20 (3.07–6.43) | |
| Graft recurrence | 7.70 (4.67–14.00) | 0.02* |
| Other site | 13.00 (6.50–24.30) | |
| Lung recurrence | 6.88 (4.67–11.10) | 0.43 |
| Other site | 13.83 (6.50–20.90) | |
| Abdominal lymph node recurrence | 8.23 (4.67–13.40) | 0.42 |
| Other site | 13.15 (6.43–16.60) | |
| Adrenal recurrence | 14.70 (3.97–32.60) | 0.63 |
| Other site | 9.10 (6.07–14.30) | |
| Bone recurrence | 6.43 (2.37–26.90) | 0.56 |
| Other site | 12.77 (6.43–15.70) | |
| Peritoneal recurrence | 3.97 (1.57–9.10) | 0.024* |
| Other site | 12.97 (6.50–15.70) | |
| Pleural recurrence | 19.80 (1.83 –) | 0.84 |
| Other site | 10.10 (6.43–14.70) | |
| Abdominal wall recurrence | 17.30 (5.37 –) | 0.32 |
| Other site | 10.10 (6.43–14.70) | |
| Single lesion at recurrence | 26.50 (14.00–38.87) | <0.0001* |
| Multiple lesions at recurrence | 6.07 (5.20–8.23) | |
| Single sites of recurrence | 13.97 (8.00–24.27) | 0.005* |
| Multiple sites of recurrence | 5.63 (3.97–8.23) | |
| Initial treatment: | <0.0001* | |
| Surgical resection | 33.57 (26.50–60.43) | |
| Percutaneous ablation (e.g., RFA) | 20.90 (13.83 –) | |
| Transarterial chemoembolization (TACE)a | 22.67 ( – ) | |
| External radiation | 10.93 (1.83–15.90) | |
| Systemic therapy | 7.70 (5.43–11.10) | |
| Supportive care | 2.05 (0.57–3.97) | |
| Treatment group: | <0.0001* | |
| Surgery or ablation | 31.93 (24.27–56.63) | |
| Other treatments | 8.00 (5.93–12.97) | |
| Supportive care | 2.05 (0.57–3.97) | |
| RETREAT score < 5 | 16.30 (5.53–28.80) | 0.015* |
| ≥5 | 8.23 (5.93–13.40) |
HCC, hepatocellular carcinoma; CI, confidence interval; HCV, hepatitis C virus; LT, liver transplantation; AFP, alpha-fetoprotein; UCSF, University of California San Francisco; ALT, alanine transaminase; ALP, alkaline phosphatase; RFA, radiofrequency ablation; RETREAT, Risk Estimation of Tumor Recurrence After Transplant.
* P < 0.05.
There was only one patient who initially treated with TACE in our study.
In multivariate analysis, poorly differentiated histology on the explant, bilirubin ≥1.2 mg/dL at recurrence, albumin <3.5 mg/dL at recurrence, AFP at recurrence ≥1000 ng/mL, and peritoneal recurrence were independent predictors of poor survival, whereas a better survival was noted in patients with sirolimus exposure (Table 6 and Figure 2).
Table 6.
Multivariate Analysis on Significant Predictors for Survival After HCC Recurrence.
| Parameter | Hazard ratio (95% CI) | P value |
|---|---|---|
| Poorly differentiated histology on the explant | 1.96 (1.08–3.58) | 0.027* |
| Time to recurrence ≥ 12 months | 0.58 (0.33–1.01) | 0.056 |
| Bilirubin at recurrence ≥ 1.2 mg/dL | 2.47 (1.12–5.43) | 0.025* |
| Albumin at recurrence < 3.5 mg/dL | 2.13 (1.16–3.85) | 0.014* |
| AFP at recurrence ≥ 1000 ng/mL | 2.96 (1.38–6.34) | 0.005* |
| Graft recurrence | 1.72 (0.97–3.06) | 0.065 |
| Peritoneal recurrence | 3.20 (1.19–8.62) | 0.022* |
| Single lesion at recurrence | 0.71 (0.36–1.39) | 0.314 |
| Multiple sites at recurrence | 1.26 (0.56–2.87) | 0.575 |
| Sirolimus use | 0.32 (0.18–0.56) | <0.0001* |
| RETREAT score ≥ 5 | 1.30 (0.73–2.31) | 0.369 |
HCC, hepatocellular carcinoma; CI, confidence interval; AFP, alpha-fetoprotein; RETREAT, Risk Estimation of Tumor Recurrence After Transplant.
* P < 0.05.
Figure 2.
Factors predicting survival after recurrence of hepatocellular carcinoma post-LT in 96 patients.
Discussion
LT is a widely accepted therapeutic option for patients with cirrhosis complicated by HCC. Despite careful candidate selection, recurrence of HCC after LT is around 10–20%,4,10,12 and median overall survival after recurrence has been of less than two years.11,13 The study from the United Network for Organ Sharing (UNOS) database between 2002 and 2013 to evaluate predictors of HCC recurrence after LT found recurrence rate of around 11.5% (n = 321/2794) and with significantly decreased overall survival (P < 0.001).12 The bridging local-regional therapy group exhibited lower recurrence, while patient's age >60 years, serum AFP >400 mg/L, and microvascular invasion were independent risk factors for tumor recurrence.12 An experience from the University of California, Los Angeles (UCLA) between 1984 and 2013 (recurrence = 117/865) noted significant predictors of HCC recurrence such as tumor grade/differentiation, macrovascular and microvascular invasion, nondownstaged tumors outside Milan criteria, maximum tumor diameter, and maximum AFP levels.14 Of note, our similar and large single center experience validates the high-risk features for HCC recurrence (e.g., microvascular invasion, tumors beyond Milan criteria, number of lesions, maximum size of tumor on the explant) and peak levels of post-transplant AFP. A unique feature of our experience is that we also evaluated any exposure to sirolimus that seemed to be beneficial while we admit that this is a retrospective analysis and with no predefined criteria for the use of sirolimus following transplant or after recurrence of HCC.
Previous studies have noted the negative impact on survival after recurrence of several prognostic factors such as tumor size, differentiation of the original tumor, and the presence of bone recurrence, while accessibility to surgical treatment, the absence of bone metastases, and late recurrence (>1 year) were associated with longer survival after recurrence.7,15,16 Shin et al (n = 28) noted that independent prognostic factors affecting survival after recurrence in adult living donor LT for HCC were major vascular invasion, a poorly differentiated tumor, unresectable disease, and bone metastases.16 In our large experience spanning several years, there was a significant relationship between poorly differentiated tumor on explant pathology and peritoneal recurrence on survival after recurrent HCC in the multivariate analysis; however, bone metastasis did not influence survival. Further, longer time to recurrence (≥12 months) also favorably impacted postrecurrence survival in univariate analysis, and this significance was nearly apparent in our multivariate analysis (p = 0.056). The impact of time to recurrence on survival is consistent with another observation by Sapisochin et al (n = 121), which noted that early recurrence (<12 months) was associated with poorer prognosis for survival after HCC recurrence.17
Not surprisingly, AFP ≥1000 ng/dL at the time of recurrence was independently associated with poor survival in recurrent HCC after LT, because a markedly elevated AFP is known to be a characteristic of aggressive tumor behavior and thus poor outcomes,10,17,18 and this has been validated in various clinical settings, including curative resection19 or palliative treatment.20 Of note, high bilirubin (≥1.2 mg/dL) and low albumin (<3.5 mg/dL) at the time of recurrence were factors significantly associated with shorter survival. It is conceivable that higher bilirubin levels were a reflection of graft dysfunction at recurrence; however, other parameters such as alanine transaminase (ALT), alkaline phosphatase (ALP), and international normalized ratio (INR) were not significantly associated with survival. Low albumin is likely a reflection of poor nutritional status and is in line with finding of lower survival in those with poor nutritional status as noted by others.21
The RETREAT score for HCC recurrence after LT is a validated risk score for predicting HCC recurrence and is based on factors of microvascular invasion on explant, AFP at time of LT, and the sum of the largest viable tumor diameter (cm) and numbers of viable tumors on the explant.20 A RETREAT score ≥5 (range 0–8) is associated with five-year post-LT recurrence risk of greater than 75%.22 As previously described, we also found these factors significant for predicting HCC recurrence in our study. A unique part of our analysis is that we attempted to evaluate whether this score could have predictive value on survival after recurrence and noted that it was associated with poor survival (p = 0.015) in the univariate analysis; however, this was not significant in a multivariate analysis. Thus, as of now, the RETREAT score is useful in predicting post-LT recurrence risk for HCC, but the utility of the scoring system to predict survival after HCC recurrence needs further evaluation.
From our univariate analysis, we demonstrated that treatment modality of recurrent HCC after LT had a significant effect on survival. Patients treated with surgical resection or percutaneous ablation had a longer median survival, relative to other HCC treatment modalities (e.g. TACE, external radiation, systemic therapy). However, there is inherent bias in this observation as surgical resection and percutaneous ablation were predominantly applied to patients with a single lesion at recurrence, whereas other modalities were applied to multiple lesions. Presumably, the difference in survival observed with different treatment modalities may be due to the less aggressive nature of tumors presenting with a single lesion at recurrence, rather than the effect of treatment itself. However, given the significant difference in survival between the treatment groups, which is also consistent with data from previous studies suggesting resection as being associated with improved survival,10,13,15 we believe that surgical resection and/or percutaneous ablation should be attempted, if feasible, for recurrent HCC regardless of whether it is at a metastatic site or in the liver. At our center, 31 of the 96 patients had either surgical resection or RFA.
Management of immunosuppression after HCC recurrence is another option to improve survival in patients with recurrent HCC after LT. Sirolimus, the mammalian target of rapamycin (mTOR) inhibitor, known for its anti-angiogenesis,23 anti-proliferative, and anti-neoplastic effects,24 has been associated with favorable outcomes in patients undergoing LT and had HCC.25 A large prospective randomized trial on sirolimus in LT recipients with HCC, the Sirolimus in Liver Transplant Recipients with HCC study (SiLVER), noted better recurrence-free survival and overall survival in the first 3–5 years after LT, especially in low-risk patients with tumor features within Milan criteria.25 Accordingly, our study also supports this benefit on both lower risk of HCC recurrence and survival after HCC recurrence in patients treated with sirolimus-based immunosuppression after LT. However, large prospective and randomized trials are needed to generate robust data to confirm this observation.
This study has limitations, in that it is retrospective in nature and has bias on selection of treatment modality. Yet, it is a large single-center US series that reports of survival after HCC recurrence spanning several years of experience during which there has been evolution of various treatment modalities. Experiences published thus far have been primarily from Europe and with fewer experiences from the US, particularly in the context of rapidly advancing therapeutic modalities.7,10,13,25, 26, 27 A large UNOS database analysis noted a recurrence rate of 11.5% (321 of 2794 LT for HCC) and evaluated the predictors of recurrence but did not assess the presentation, course of recurrence, and survival after recurrence, given the lack of such data in the UNOS database;12 thus, our study is even more relevant, as it provides postrecurrence data from a large single-center cohort spanning several years.
It can be argued that surgical resection and/or percutaneous ablation were performed in the patients with a better general condition, which is inherently associated with high survival probability. Surgical resection has been noted to be the treatment option independently associated with longer survival for recurrent HCC after LT by others as well, and thus, a prospective randomized-controlled trial for recurrent HCC may not be ethical and feasible. As such, we believe that surgical resection should be considered in patients with recurrent HCC post-LT, if possible, after an appropriate case-by-case selection.
Authors’ contributions
Sirina Ekpanyapong MD – intellectual genesis, data acquisition, data analysis, tables creation, manuscript writing, and revision.
Neil Philips – data acquisition, research coordinator.
Bao-Li Loza PhD – data analysis, figures creation.
Peter Abt MD, Emma E. Furth MD, Rashmi Tondon MD, Vandana Khungar MD MSc, Kim Olthoff MD, and Abraham Shaked MD PhD – critical manuscript review.
Maarouf A. Hoteit MD – intellectual genesis, data acquisition, critical manuscript review.
K. Rajender Reddy MD – intellectual genesis, critical manuscript review, manuscript revision.
Conflicts of interest
The authors have none to declare.
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