Factors predicting survival after post-transplant hepatocellular carcinoma recurrence

Background

Although factors associated with an increased risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been extensively studied, the history of patients with a post-transplant recurrence is poorly known.

Methods

Patients experiencing a post-transplant HCC recurrence from 1996 to 2011 in two transplant programs were included. Demographic, transplant, and post-recurrence variables were assessed.

Results

Thirty patients experienced an HCC recurrence–22 men and 8 women with a mean age of 55 ± 6 years. Sixteen (53 %) were outside the Milan criteria at the time of transplantation. Most recurrences (60 %) appeared within the first 18 months after transplantation, ranging between 1.7 and 109 months (median 14.2 months). Mean post-recurrence survival was 33 ± 31 months. On univariate analysis, total tumor volume (TTV; p = 0.047), microvascular invasion (p = 0.011), and time from transplant to recurrence (p = 0.001) predicted post-recurrence survival. On multivariate analysis, both time from transplant to recurrence (p = 0.001) and history of rejection (p = 0.043), but not the location of the recurrence or the type of recurrence treatment, predicted post-recurrence survival.

Conclusion

This study suggests that patients with early post-transplant HCC recurrence have worse outcomes. Those with a history of graft rejection have better survivals, possibly due to more active anti-cancer immunity.     

Optimal duration of the early and late recurrence of hepatocellular carcinoma after hepatectomy

AIM: To determine the best cut-off value between the early and late recurrence periods after the initial recurrence of hepatocellular carcinoma(HCC).METHODS: The clinical records of 404 patients who underwent macroscopic curative hepatectomy for HCC between 1980 and 2010 were retrospectively examined. We divided the 252 patients experienced a recurrence of HCC into two groups, the early and late recurrence groups using the minimum P-value approach. Factors for early recurrence were investigated using all 404 patients, and factors related to late recurrence were investigated in the patients who were confirmed to be recurrence free at the end of the early recurrence period.RESULTS: For the 252 patients who experienced a recurrence, the optimal cut-off value for differentiating early and late recurrence based on the overall survival after initial recurrence was 17 mo(5-year overall survival after initial recurrence: 15.4% vs 36.3%, P = 0.000018). Cox proportional hazard analysis identified early recurrence(P = 0.003) as one of the independent prognostic factors associated with overall survival after initial recurrence. A logistic regression model showed that an alpha-fetoprotein level > 100 ng/m L(P < 0.001), multiple HCC(P < 0.001), serosal invasion(P = 0.031), and microvascular invasion(P = 0.012) were independent factors associated with early recurrence, whereas the only independent factor related to late recurrence was liver cirrhosis(P = 0.002).CONCLUSION: Seventeen months after hepatectomy is a useful cut-off value between early and late recurrence of HCC based on the prognosis and different etiologies.     

Positive glypican-3 expression in early hepatocellular carcinoma predicts recurrence after hepatectomy

Background

Glypican-3 (GPC3) is a new prognostic factor after curative hepatectomy in patients with hepatocellular carcinoma (HCC), and the expression of GPC3 is known to be associated with postoperative metastasis. However, the role of GPC3 in patients with early HCC remains unknown.

Methods

We retrospectively studied 55 patients with early HCC (total 99 nodules) who underwent initial hepatectomy between 1995 and 2010. Clinicopathological features and surgical outcomes were compared in relation to GPC3 expression.

Results

The GPC3-positive expression was seen in 28 of 55 patients (50.9 %) with early HCC (44 of 99 nodules). The GPC3-positive expression was significantly associated with hepatitis C virus (HCV) infection (P = 0.0019) and with multiple early HCCs (P < 0.0001). The 5-year disease-free survival rate was significantly lower in patients with GPC3-positive early HCC (27 %) than in patients with GPC3-negative early HCC (62 %, P = 0.0036). The GPC3 expression was a significant independent prognostic factor for disease-free survival. However, it showed no significant difference in overall survival.

Conclusions

The GPC3 expression is capable to be a new prognostic factor for disease-free survival in patients with early HCC.     

Predictive value of gross classification of hepatocellular carcinoma on recurrence and survival after hepatectomy

BACKGROUND/AIM: A new gross classification of hepatocellular carcinoma in which Eggel's nodular type is subclassified into type 1 (single nodular type), type 2 (single nodular type with extranodular growth), and type 3 (contiguous multinodular type) has been widely used in Japan. The aim of the study was to determine whether this classification is correlated with patient outcome. METHODS: Sixty-five resected hepatocellular carcinoma nodules (< or = 5 cm) were classified using this new classification. RESULTS: The 65 tumors were classified into 30 type 1 (46%), 20 type 2 (31%), and 15 type 3 (23%) hepatocellular carcinomas. The rate of microscopic vascular invasion significantly increased from type 1 to type 2, and to type 3 tumors (p=0.03). Kaplan-Meier estimates showed that type 1 was significantly associated with lower recurrence rate (type 1 vs. type 2, p=0.01; type 1 vs. type 3, p=0.004; log-rank test), and higher disease-specific survival (type 1 vs. type 2, p=0.02; type 1 vs. type 3, p=0.002). Cox's proportional-hazards model demonstrated that type 1 was an independent factor for low risk of recurrence (p=0.002) and low risk of disease-specific death (p=0.02). CONCLUSION: The gross classification of hepatocellular carcinoma is of clinical value in predicting patient outcome.     

Predictive factors affecting early recurrence after hepatectomy for hepatocellular carcinoma in 5-year survivors

BACKGROUND/AIMS: This study was undertaken to establish a therapeutic strategy for long-term recurrence-free survival in hepatocellular carcinoma (HCC) patients treated by hepatectomy by determining the factors that predict intrahepatic recurrence. METHODOLOGY: This study included 72 patients who survived more than 5 years after hepatectomy for HCC. Based on the interval between hepatectomy and intrahepatic recurrence, they were classified into 3 groups: those with early recurrence within 2 years after surgery (n=15), those with recurrence between 2 and 5 years (n=18), and those without recurrence within 5 years (n=39). Twenty-six parameters concerning host-related, tumor-related, treatment-related factors, and postoperative levels of serum transaminases were evaluated. RESULTS: Among host-related and tumor-related factors, serum albumin level, serum levels of transaminases, indocyanine green retention rate at 15 minutes, tumor number, intrahepatic metastasis and TNM stage were determined to be significantly different between the patients with recurrence within 5 years and those without recurrence. Among treatment-related factors, curability was highly associated with recurrence. The period until increase in the levels of transaminases after surgery was significantly shorter in patients with recurrence compared to the patients without recurrence. CONCLUSIONS: Curative operation minimizing intrahepatic metastasis and postoperative anti-inflammatory treatment lowering the occurrence of multicentric carcinogenesis are useful therapeutic strategies for achieving long-term recurrence-free survival for HCC patients treated with surgery.     

原发性肝癌术后复发的综合防治

原发性肝癌(以下简称肝癌)是世界第六大癌症,癌症死因顺位第三位.中国是肝癌的高发区,全世界每年的新发患者我国占一半以上.手术切除仍是目前治疗肝癌的首选手段,然而较高的术后复发率已成为影响患者疗效和获得长期生存的瓶颈.如何有效地预防及治疗术后复发,成为能否进一步提高肝癌治疗效果的关键,也是目前临床研究的热点和难点.本文结合本单位的临床工作实践探讨肝癌术后复发的预防和治疗对策.     

Preoperative inflammation-based markers predict early and late recurrence of hepatocellular carcinoma after curative hepatectomy

BACKGROUND:Recurrence of hepatocellular carcinoma(HCC) after curative resection remains a major cause of treatment failure and tumor-related death.Patterns of HCC recurrence can be categorized into early recurrence and late recurrence which have different underlying mechanisms.In this study,we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC.METHODS:A retrospective analysis of 223 patients who underwent curative hepatectomy for HCC was performed.Preoperative inflammation-based factors including neutrophil/lymphocyte ratio(NLR),platelet/lymphocyte ratio,γ-glutamyl transferase/alanine aminotransferase ratio,aspartate aminotransferase/platelet ratio index(APRI) and prognostic nutritional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analysis to identify independent prognostic factors.By combining risk factors,predictive models were established to distinguish populations at high risk of early or late recurrence.RESULTS:Age ≤50 years,resection margin ≤1 cm,TNM stage III-IV,NLR2.75,APRI0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recurrence.Patients with three or more risk factors were at significant higher risk of early recurrence.APRI0.23 and positive hepatitis B e antigen(HBe Ag) were independent risk factors of late recurrence,the coexistence of high APRI and positive HBe Ag increased the risk of late recurrence.CONCLUSIONS:Preoperative inflammation-based prognostic factors predict early and late recurrence of HCC after curative resection.Different prognostic factor combinations distinguish high-risk populations of early or late HCC recurrence.     

Preoperative inlfammation-based markers pre-dict early and late recurrence of hepatocellular carcinoma after curative hepatectomy

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after curative resection remains a major cause of treat-ment failure and tumor-related death. Patterns of HCC recur-rence can be categorized into early recurrence and late recur-rence which have different underlying mechanisms. In this study, we investigated if simple inlfammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC.
METHODS: A retrospective analysis of 223 patients who un-derwent curative hepatectomy for HCC was performed. Pre-operative inlfammation-based factors including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio,γ-glutamyl transferase/alanine aminotransferase ratio, aspartate amino-transferase/platelet ratio index (APRI) and prognostic nutri-tional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analy-sis to identify independent prognostic factors. By combining risk factors, predictive models were established to distinguish populations at high risk of early or late recurrence.
RESULTS: Age≤50 years, resection margin≤1 cm, TNM stage III-IV, NLR>2.75, APRI>0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recur-rence. Patients with three or more risk factors were at signiif-cant higher risk of early recurrence. APRI>0.23 and positive hepatitis Be antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence.
CONCLUSIONS: Preoperative inlfammation-based prognostic factors predict early and late recurrence of HCC after curative resection. Different prognostic factor combinations distin-guish high-risk populations of early or late HCC recurrence.     

Gender disparity in hepatocellular carcinoma recurrence after curative hepatectomy

Introduction and objectivesWhether there is gender disparity in the recurrence of hepatocellular carcinoma (HCC) has been not fully addressed. This study aimed to investigate the impact of gender on HCC recurrence following curative hepatectomy.Patients and methodsThis retrospective cohort study included 1087 patients with HCC (917 males, 170 females) who underwent curative hepatectomy. Cox regression models were constructed to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the risk parameters associated with HCC recurrence. In the sensitivity analysis, subgroup analysis, and propensity score matching (PSM) analysis were used. Logistic regression models were used to assess the odds ratio (OR) and 95% CI of the risk parameters related to early and late recurrence.ResultsMale patients showed significantly higher risk for HCC recurrence than females, in both multivariate Cox regression analysis (HR [95% CI] = 1.480 [1.084–2.020], P = 0.014) and PSM analysis (HR [95% CI] = 1.589 [1.093–2.312], P = 0.015). Higher risk of HCC recurrence was again found in males in the subgroup analysis, but the effect of male versus female gender on HCC recurrence did not depend on any selected subgroups (all P for interaction > 0.05). Gender was an independent risk factor for early recurrence (OR [95% CI] = 1.864 [1.215–2.936], P = 0.006), but not for late recurrence.ConclusionsThere is gender disparity in the recurrence of patients with HCC after curative hepatectomy: males had a higher risk for HCC recurrence than females.     

Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy

BACKGROUND/AIMS: We conducted a retrospective cohort study to investigate factors to early and late phase recurrence of hepatocellular carcinoma (HCC). METHODS: The study population consisted of 249 patients including 157 with cirrhosis who underwent hepatectomy for HCC. The endpoint was time-to-recurrence. Using a Cox regression model, factors to early and late phase recurrences were investigated censoring recurrence-free patients at the 2-year time point and in patients without recurrence at 2 years. RESULTS: Actuarial probability of overall recurrence at 1, 3, and 5 years were 0.301, 0.623, and 0.790, respectively, with a median follow-up of 624 days. Early recurrence was observed in 123 out of 249 patients; while late recurrence was found in 61 out of 113 patients. Factors to early recurrence were as follows: non-anatomical resection, presence of microscopic vascular invasion, and serum alpha-fetoprotein level >or=32 ng/ml. Those contributing to late phase recurrence were higher grade of hepatitis activity, multiple tumors, and gross tumor classification. CONCLUSIONS: Variables associated with metastatic recurrence were factors to early phase recurrence; whereas those related with elevated carcinogenesis contributed to late phase recurrence, thus providing an epidemiological evidence that different mechanisms, i.e. metastasis and de novo, are involved in intrahepatic recurrence after hepatectomy for HCC.     

Preoperative serum liver enzyme markers for predicting early recurrence after curative resection of hepatocellular carcinoma

<正>BACKGROUND:Early recurrence of hepatocellular carcinoma(HCC)is associated with worse prognosis after liver resection This study aimed to investigate the prognostic value of com mon liver enzyme markers in HCC early recurrence after cu rative hepatectomy and to establish a simple predictive model for HCC early recurrence.     

Hepatic function immediately after hepatectomy as a significant risk factor for early recurrence in hepatocellular carcinoma

BACKGROUND/AIMS: The aim of this study was to clarify the significant risk factors as they relate to early recurrence after hepatectomy in cirrhotic patients with hepatocellular carcinoma (HCC). METHODOLOGY: We retrospectively investigated 42 cirrhotic patients undergoing hepatectomy for a single HCC. We compared the clinicopathologic features of 14 patients with early intrahepatic recurrence (recurrence was detected within 1 year after hepatic resection; Group 1) with 28 patients without recurrence or with late intrahepatic recurrence (recurrence was confirmed more than 1 year after hepatic resection; Group 2). RESULTS: There were no significant differences in the pre-operative and intra-operative clinical background data or pathological data between the 2 groups. Regarding recurrence pattern, although not significant, the incidence of intrahepatic metastasis in Group 1 (85.7%) was higher than in Group 2 (50.0%). Maximum values of total bilirubin and albumin within 7 days after hepatectomy for patients in Group 2 were significantly better than those in Group 1. Aspatate aminotransferase (AST) and alanine aminotransferase (ALT) immediately after hepatectomy in Group 1 were also higher than in Group 2, although statistically insignificant. The overall 1-year and 3-year survival rates between Group 1 versus Group 2 were 85.7% versus 100% (p < 0.01) and 57.2% versus 90.0% (p < 0.01), respectively. CONCLUSIONS: Hepatic functional damage immediately after hepatectomy is as significant risk factor for early intrahepatic recurrence in cirrhotic HCC. Careful perioperative management of hepatic function may therefore be important in preventing early recurrence and prolonging survival.     

Ten-year survival of patients with hepatocellular carcinoma after hepatectomy

BACKGROUND/AIMS: The characteristics in patients with hepatocellular carcinoma who survive more than 10 years after hepatectomy remain unclear. METHODOLOGY: Eighty-five cases of hepatocellular carcinoma were retrospectively identified as short-term survivors (S-group: <5 years, n=41), medium-term survivors (M-group: > or =5 and <10 years, n=25), and long-term survivors (L-group: > or =10 years, n=19) to examine the clinicopathologic factors for the 10-year survival after curative hepatectomy. RESULTS: In the L-group, platelet count and albumin level were higher and total bilirubin level was lower than those in the S-group. In the S-group, the total bilirubin level was higher and vascular invasion was more frequent than those in the M-group. Multiple regression analysis revealed that only host-related factors such as age, albumin level, and total bilirubin level were selected as significant factors to determine the 10-year survival. However, no tumor-related factor was selected. CONCLUSIONS: The present study suggests that the important factor linked to the 10-year survival of hepatocellular carcinoma patients is the host-related factor, but not the tumor-related factor. Especially, younger age, higher albumin level, and lower total bilirubin level are quite important to determine the 10-year survival.     

Preoperative predictors of short-term survival after hepatectomy for multinodular hepatocellular carcinoma

AIM: To investigate preoperative factors associated with poor short-term outcome after resection for multinodular hepatocellular carcinoma (HCC) and to assess the contraindication of patients for surgery.METHODS: We retrospectively analyzed 162 multinodular HCC patients with Child-Pugh A liver function who underwent surgical resection. The prognostic significance of preoperative factors was investigated by univariate analysis using the log-rank test and by multivariate analysis using the Cox proportional hazards model. Each independent risk factor was then assigned points to construct a scoring model to evaluate the indication for surgical intervention. A receiver operating characteristics (ROC) curve was constructed to assess the predictive ability of this system.RESULTS: The median overall survival was 38.3 mo (range: 3-80 mo), while the median disease-free survival was 18.6 mo (range: 1-79 mo). The 1-year mortality was 14%. Independent prognostic risk factors of 1-year death included prealbumin < 170 mg/L [hazard ratio (HR): 5.531, P < 0.001], alkaline phosphatase > 129 U/L (HR: 3.252, P = 0.005), α fetoprotein > 20 μg/L (HR: 7.477, P = 0.011), total tumor size > 8 cm (HR: 10.543; P < 0.001), platelet count < 100 × 10⁹/L (HR: 9.937, P < 0.001), and γ-glutamyl transpeptidase > 64 U/L (HR: 3.791, P < 0.001). The scoring model had a strong ability to predict 1-year survival (area under ROC: 0.925, P < 0.001). Patients with a score ≥ 5 had significantly poorer short-term outcome than those with a score < 5 (1-year mortality: 62% vs 5%, P < 0.001; 1-year recurrence rate: 86% vs 33%, P < 0.001). Patients with score ≥ 5 had greater possibility of microvascular invasion (P < 0.001), poor tumor differentiation (P = 0.003), liver cirrhosis with small nodules (P < 0.001), and intraoperative blood transfusion (P = 0.010).CONCLUSION: A composite preoperative scoring model can be used as an indication of prognosis of HCC patients after surgical resection. Resection should be considered with caution in patients with a score ≥ 5, which indicates a contraindication for surgery.     

Defining and predicting early recurrence after liver resection of hepatocellular carcinoma: a multi-institutional study

BackgroundA clear definition of “early recurrence” after hepatocellular carcinoma (HCC) resection is still lacking. This study aimed to determine the optimal cutoff between early and late HCC recurrence, and develop nomograms for pre- and postoperative prediction of early recurrence.MethodsPatients undergoing HCC resection were identified from a multi-institutional Chinese database. Minimum P-value approach was adopted to calculate optimal cut-off to define early recurrence. Pre- and postoperative risk factors for early recurrence were identified and further used for nomogram construction. The results were externally validated by a Western cohort.ResultsAmong 1501 patients identified, 539 (35.9%) were recurrence-free. The optimal length to distinguish between early (n = 340, 35.3%) and late recurrence (n = 622, 64.7%) was 8 months. Multivariable logistic regression analyses identified 5 preoperative and 8 postoperative factors for early recurrence, which were further incorporated into preoperative and postoperative nomograms (C-index: 0.785 and 0.834). The calibration plots for the probability of early recurrence fitted well. The nomogram performance was maintained using the validation dataset (C-index: 0.777 for preoperative prediction and 0.842 for postoperative prediction).ConclusionsAn interval of 8 months was the optimal threshold for defining early HCC recurrence. The two web-based nomograms have been published to allow accurate pre- and postoperative prediction of early recurrence. These may offer useful guidance for individual treatment or follow up for patients with resectable HCC.     

肝细胞癌冷冻消融术后早期复发的危险因素

目的:探讨肝细胞癌(hepatocellular carcinoma,HCC)患者冷冻消融术后影响早期复发的相关危险因素.方法:回顾分析90例直径≤5.0 cm的HCC行冷冻消融治疗后复发的患者的临床资料,分析影响冷冻消融术后早期复发的危险因素.结果:本组患者随访8-47(平均随访时间21.9±10.1)mo,共有57...     

Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses.

The purpose of this study was to clarify the factors linked to recurrence of small hepatocellular carcinomas, up to 3 cm in diameter, after hepatectomy. Fifty patients with small hepatocellular carcinomas who underwent hepatectomy between 1976 and 1988 were observed for possible recurrence for at least 2 yr. These patients were divided into two groups: 20 patients who had recurrence within 2 yr and 30 patients who had no recurrence within 2 yr. The recurrence pattern was analyzed by hepatic angiography. Statistical analysis by the chi 2 test and stepwise logistic regression showed that the risk factors linked to recurrence were (a) tumor diameter greater than 2.2 cm, (b) intracapsular infiltration of tumor cells, (c) tumor location deep in the liver, (d) macroscopical and microscopical tumor invasion into the portal vein and (e) tumor invasion into the portal vein or intrahepatic metastasis. When patients diagnosed with small hepatocellular carcinomas have any of these risk factors, postoperative adjuvant therapy and follow-up should be particularly carefully considered, since these patients are at high risk for early recurrence.