Late Recurrence Of Hepatocellular Carcinoma Research Articles

Early versus Late Recurrence of Hepatocellular Carcinoma after Surgical Resection Based on Post-recurrence Survival: An International Multi-institutional Analysis

Introduction: To define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative resection for hepatocellular carcinoma (HCC). Method: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. Results: Among 1,004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n=165, 37.2%) versus late relapse (n=278, 62.8%)(p=0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p=0.019), as well as Overall survival (OS) (median OS, 32.0 versus 74.0 months, p< 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p=0.003) sites. Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p=0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p< 0.001). Conclusions: Eight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes.

The optimal timing and management of hepatitis B and C in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer related mortality worldwide, with the most common underlying etiologies being chronic hepatitis B and hepatitis C infections. Treatment of these viral hepatidities in the setting of HCC has been debated, and there is increasing study addressing this topic. Patients with advanced HCC of either etiology are unlikely to benefit from antiviral treatments, and futility should be considered prior to starting antiviral therapy. Hepatitis B treatment has demonstrated improved survival, decreased risk of hepatitis B reactivation, and decreased risk of late HCC recurrence. The mainstay treatment of chronic hepatitis B has been nucleos(t)ide analogues (NAs), and in the setting of HCC, entecavir and tenofovir are preferred given their higher potency and barriers to resistance. Those who were already on a NAs at the time of HCC diagnosis should be continued on them regardless of the HCC management planned. Patients who are suitable candidates to start NAs should start them at the time of HCC diagnosis. Direct-acting antivirals (DAAs) are the first line therapies for hepatitis C. Unlike with hepatitis B, those with HCV-associated HCC are recommended to start treatment 3-6 months after complete treatment of their HCC, given lower rates of sustained virologic response (SVR) with active HCC. There are also controversial concerns about DAAs contributing to a more aggressive HCC phenotype, but data are limited by retrospective studies, and more recent retrospective studies are more reassuring. In transplant candidates, starting DAAs may be deferred until after transplant depending on median regional wait times, availability of HCV positive organs, and the degree of the patient's liver dysfunction. Overall, in patients with HCC from hepatitis B or C, treatment of the underlying viral hepatitis should be considered unless advanced stage limits benefits and results in futility.

Late recurrence of hepatocellular carcinoma after radiofrequency ablation: a multicenter study of risk factors, patterns, and survival.

This study aims to determine the risk factors, patterns, and long-term survival outcomes of late recurrence after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) within the Milan criteria and develop a nomogram to predict the recurrence-free survival (RFS). This retrospective study included patients with HCC within the Milan criteria, who received RFA at three hospitals in China from January 2011 to December 2016. The clinical variables were assessed by univariate and multivariate Cox regression analyses. A total of 398 patients were included. The median follow-up was 58.7months (range: 24.1-96.0). Ninety-eight patients had late recurrence. Furthermore, 14 patients (14.29%) had local tumor progression (LTP) alone, 43 patients (43.88%) had intrahepatic distant recurrence (IDR) alone, 15 patients (15.31%) had extrahepatic recurrence (ER) alone, three patients (3.06%) had both LTP and IDR, six patients (6.12%) had both LTP and ER, and 17 patients (17.35%) had both IDR and ER. Patients without late recurrence had better long-term overall survival (OS) compared to those with late recurrence (p < 0.001). Male gender, multiple tumors, and cirrhosis were the independent risk factors of late recurrence. A well-discriminated and calibrated nomogram was constructed to predict the probability of RFS. Male gender, multiple tumors, and cirrhosis are the independent risk factors of late recurrence after RFA for HCC within the Milan criteria. Late recurrence might mainly occur from de novo HCC under the background of cirrhosis. An individualized surveillance and prevention strategy for HCC patients after RFA should be developed. • In the present retrospective study of 398 patients, male gender, multiple tumors, and cirrhosis were the independent risk factors of late recurrence (> 2years) of HCC after RFA. • The most common pattern of late recurrence was intrahepatic distant recurrence alone (n = 43, 43.88%). Late recurrence might mainly occur from de novo HCC under the background of cirrhosis. • A prognostic nomogram was built to predict the individualized recurrence-free survival after RFA, which achieved good calibration and discriminatory ability with a concordance index of 0.763.

Change in the Recurrence Pattern and Predictors over Time after Complete Cure of Hepatocellular Carcinoma.

Background/AimsWe investigated changes in recurrence rates and significant recurrence predictors over time after complete cure of hepatocellular carcinoma (HCC).MethodsA total of 1,491 patients with first-time diagnosis of Barcelona Clinic Liver Cancer stage A HCC, completely cured by treatment between 2007 and 2016, were recruited from two Korean tertiary institutes.ResultsThe mean age of the population (1,144 men and 347 women) was 58.6 years. Of the total population, 914 patients (61.3%) had liver cirrhosis. Nine-hundred and forty-one (63.1%) and 550 (36.9%) patients were treated with surgical resection and radiofrequency ablation (RFA), respectively. One-year cumulative incidences of HCC recurrence were 14.3%, 9.9%, and 5.1% from the time of treatment, 3 years after treatment, and 5 years after treatment, respectively. Upon multivariate analysis, multiple tumors, maximal tumor size ≥3 cm, and high Model for End-Stage Liver Disease scores were independently associated with increased HCC recurrence risk from the time of treatment and 1 and 2 years after curative treatment (all p<0.05, except for maximal tumor size ≥3 cm for recurrence 2 years after treatment). Meanwhile, liver cirrhosis and RFA were independently associated with the increased HCC recurrence risk for almost all time points (liver cirrhosis all p<0.05; RFA all p<0.005 except for recurrence from 5 years after treatment).ConclusionsThe recurrence rate of HCC after curative treatment gradually decreased over time. Two years after treatment, when tumor-related factors lose their prognostic implications, may be used as a cutoff to define the boundary between early and late recurrence of HCC. (Gut Liver 2021;15-429)

Early Versus Late Recurrence of Hepatocellular Carcinoma After Surgical Resection Based on Post-recurrence Survival: an International Multi-institutional Analysis

BackgroundTo define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative resection for hepatocellular carcinoma (HCC). MethodsPatients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. ResultsAmong 1004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n = 165, 37.2%) versus late relapse (n = 278, 62.8%) (p = 0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p = 0.019), as well as overall survival (OS) (median OS, 32.0 versus 74.0 months, p < 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p = 0.003) sites and were less likely to have the recurrence treated with curative intent (33.8% vs. 45.7%, p = 0.08). Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p = 0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p < 0.001). ConclusionsEight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes.

Novel Prognostic Nomograms for Predicting Early and Late Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy.

AimHepatectomy is the main curative method for patients with hepatocellular carcinoma (HCC) in China. Unfortunately, high recurrence rate after hepatectomy poses negative impact on the prognosis of patients. This study aimed to develop prognostic nomograms to predict early recurrence (ER) and late recurrence (LR) of HCC after curative hepatectomy.Patients and MethodsTotal of 318 HCC patients undergoing curative hepatectomy from January 2012 to January 2018 were retrospectively recruited. Potential risk factors that were significant for predicting ER and LR in univariate analysis were selected for multivariate survival model analysis using the backward stepwise method. Risk factors identified in multivariate analysis were used to develop nomograms to predict ER and LR. The nomogram was internally validated using 2,000 bootstrap samples from 75% of the original data.ResultsAmong 318 patients, 164 showed postoperative recurrence, of which 140 and 24 had ER (≤2 years) and LR (>2 years), respectively. Multivariate analysis showed that age, Hong Kong Liver Cancer Stage, albumin-bilirubin, METAVIR fibrosis grade, and microvascular invasion were risk factors of ER for HCC after curative hepatectomy. The AUC of the ROC curve for ER in the development set (D-set) was 0.888 while that in the validation set (V-set) was 0.812. Neutrophil/lymphocyte ratio and glypican-3 (+) were risk factors for LR in HCC patients after curative hepatectomy. The AUC of the ROC curve for LR predictive nomogram that integrated all independent predictors was 0.831. The AUC of the ROC curve for LR in the D-set was 0.833, while that for LR in the V-set was 0.733. The C-index and AUC of ROC for the proposed nomograms were more satisfactory than three conventional HCC staging systems used in this study.ConclusionWe developed novel nomograms to predict ER and LR of HCC patients after curative hepatectomy for clinical use to individualize follow-up and therapeutic strategies.

Repeat hepatectomy for early and late recurrence of hepatocellular carcinoma: A multicenter study with propensity score matching analysis

Repeat hepatectomy for early and late recurrence of hepatocellular carcinoma: A multicenter study with propensity score matching analysis

Predictive value of spleen stiffness in hepatocellular carcinoma

In their Letter to the Editor, Wei et al . address on the role of spleen stiffness measurement (SSM) for predicting the late recurrence (>24 months post-surgery) of hepatocellular carcinoma (HCC) after resection (1). They comment on a recently published manuscript by Marasco and colleagues, who could show that spleen stiffness measured by transient elastography was the only predictor of late HCC recurrence after surgery (2).

Repeat hepatectomy for patients with early and late recurrence of hepatocellular carcinoma: A multicenter propensity score matching analysis

BackgroundRepeat hepatectomy is a feasible treatment modality for intrahepatic recurrence after hepatectomy of hepatocellular carcinoma, yet the survival benefit remains ill-defined. The objective of the current study was to define long-term, oncologic outcomes after repeat hepatectomy among patients with early and late recurrence. MethodsPatients undergoing curative-intent repeat hepatectomy for recurrent hepatocellular carcinoma were identified using a multi-intuitional database. Early and late recurrence was defined by setting 1 year after initial hepatectomy as the cutoff value. Patient clinical characteristics, overall survival, and disease-free survival were compared among patients with early and late recurrence before and after propensity score matching. ResultsAmong all the patients, 81 had early recurrence and 129 had late recurrence from which 74 matched pairs were included in the propensity score matching analytic cohort. Before propensity score matching, 5-year overall survival and disease-free survival after resection of an early recurrence were 41.7% and 17.9%, respectively, which were worse compared with patients who had resection of a late recurrence (57.0% and 39.4%, both P < .01). After propensity score matching, 5-year overall survival and disease-free survival among patients with early recurrence were worse compared with patients with late recurrence (41.0% and 19.2% vs 64.3% and 43.2%, both P < .01). After adjustment for other confounding factors on multivariable Cox-regression analysis, early recurrence remained independently associated with decreased overall survival and disease-free survival (hazard ratio 2.22, 95% confidence interval 1.35–3.34, P = .001; hazard ratio 1.86, 95% confidence 1.26–2.74, P = .002). ConclusionRepeat hepatectomy for early recurrence was associated with worse overall survival and disease-free survival compared with late recurrence. These data may help inform patients and selection of patients being considered for repeat hepatectomy of recurrent hepatocellular carcinoma.

Predictive validation of qualitative fibrosis staging in patients with chronic hepatitis B on antiviral therapy

The fibrosis in chronic hepatitis shows dynamic changes during antiviral therapy (AVT). We investigated whether P-I-R (progressive vs. indeterminate vs. regressive) staging is predictive of hepatocellular carcinoma (HCC) recurrence in patients with chronic hepatitis B (CHB) taking AVT who underwent resection. Patients with CHB-related HCC who underwent curative resection between 2004 and 2017 and had received ≥2 years AVT at the time of resection were eligible. Two pathologists performed P-I-R staging. In total, 104 patients with CHB-related HCC were enrolled. The mean age of the study population was 56.3 years. The mean duration of AVT at the time of resection was 62.6 months. During the follow-up period (mean, 45.5 months), 20 (19.2%) and 14 (13.5%) patients developed early and late recurrence of HCC, respectively. The cumulative incidence of late recurrence was significantly lower in patients with regressive patterns than in those with indeterminate and progressive patterns according to P-I-R staging (P = 0.015, log-rank test), although the cumulative incidence of overall recurrence according to P-I-R staging was similar. Hepatitis B virus DNA levels (hazard ratio [HR] = 3.200, P = 0.020) and the regressive P-I-R staging pattern (HR = 0.127, P = 0.047) independently predicted the risk of late recurrence. One-time assessment of the P-I-R staging at the time of curative resection in patients with CHB-related HCC receiving AVT independently predicted late HCC recurrence. Therefore, qualitative fibrosis assessment by P-I-R staging might be useful in predicting the outcomes of patients with CHB undergoing AVT.

Impact of margin status on long-term results of liver resection for hepatocellular carcinoma: single-center time-to-recurrence analysis.

Occult metastasis from the initial tumor and a de novo second primary hepatocellular carcinoma (HCC) were recognized as the main causes for the onset of early and late HCC recurrence, after liver resection (LR). This study aims to compare the time to recurrence after LR for HCC in which a margin ≤ 1mm or > 1mm was achieved. A single-center retrospective study involving 256 patients was conducted from June 2005 to June 2019. HCC patients resected with a radical surgical approach were investigated and stratified into groups A (resection margins ≤ 1mm) and B (> 1mm), as measured on final pathologic assessment. Kaplan-Meier estimators were used to estimate the probability of recurrence, and the log-rank test was used to compare groups. Uni- and multivariable (stepwise) Cox regression models were used to assess the effect of several HCC pathological characteristics. Twenty patients were excluded for the presence of microscopic tumor invasion at pathologic analysis (R1); 236 patients underwent radical (R0) LR, and were included in the study and divided into group A (n = 61, 26%), and group B (n = 175, 74%). No differences between the two groups were detected regarding: epidemiology, tumor characteristics, type of LR, and follow-up. The estimated probability of recurrence for group A and group B at 12 and 24months was 27% and 38%, and, 33% and 46%, respectively. Univariate and multivariable Cox regression model estimates showed that tumor grading (HR 2.1, 95% CI 1.2-3.4, p = 0.006), number of nodules (HR 1.2, 95% CI 1.0-1.4, p = 0.015), and extension of the resection (HR 1.8, 95% CI 1.0-1.1, p = 0.047) were independent risk factors for HCC recurrence, with no significant effect of margin status on time to recurrence. A R0 approach that considers a margin of resection > 1mm does not improve the likelihood of HCC recurrence. Otherwise, our experience confirms that biologic tumor characteristics are the principal factors predictive of local and systemic recurrence.

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.

Very Late Recurrence of Hepatocellular Carcinoma After Orthotopic Liver Transplantation: Presentation and Management.

Very Late Recurrence of Hepatocellular Carcinoma After Orthotopic Liver Transplantation: Presentation and Management.

Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis.

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0–A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307–0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296–8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396–7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086–0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086–0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566–24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188–8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.

Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection

Hepatocellular carcinoma (HCC) is a frequent complication of liver disease. When feasible, hepatic resection is the first-choice therapy. However, tumor recurrence complicates at least 2/3 hepatic resections at 5 years. Early recurrences are mainly tumor or treatment-related, but predictors of late recurrences are undefined. We aimed to evaluate the factors related to HCC recurrence after curative resection, with liver and spleen stiffness measurement (LSM and SSM) as markers of severity and duration of the underlying liver disease. We enrolled patients with chronic liver disease and primary HCC suitable for hepatic resection. We followed up patients for at least 30 months or until HCC recurrence. We performed uni- and multivariate analyses to evaluate the predictive role of tumor characteristics, laboratory data, LSM and SSM for both early and late recurrence of HCC. We prospectively enrolled 175 patients. Early HCC recurrence at multivariate analysis was associated with viral etiology, HCC grading (3 or 4), resection margins <1 cm and being beyond the Milan criteria. HCC late recurrence at univariate analysis was associated with esophageal varices (hazard ratio [HR] 3.321, 95% CI 1.564-7.053), spleen length (HR 3.123, 95% CI 1.377-7.081), platelet/spleen length ratio if <909 (HR 2.170, 95% CI 1.026-4.587), LSM (HR 1.036, 95% CI 1.005-1.067), SSM (HR 1.046, 95% CI 1.020-1.073). HCC late recurrence at multivariate analysis was independently associated only with SSM (HR 1.046, CI 1.020-1.073). Late HCC recurrence-free survival was significantly different according to the SSM cut-off of 70 kPa (p = 0.0002). SSM seems to be the only predictor of late HCC recurrence, since it is directly correlated with the degree of liver disease and portal hypertension, both of which are involved in carcinogenesis. The main result of this study is that spleen stiffness measurement, evaluated by transient elastography, seems to be the only predictor of the late recurrence of hepatocellular carcinoma, defined as recurrence after 24 months from liver resection. Indeed, spleen stiffness measurement is directly correlated with the degree of liver disease and portal hypertension, which are both involved in carcinogenesis.

Clinical Features and Surveillance of Very Late Hepatocellular Carcinoma Recurrence After Liver Transplantation.

BackgroundThis study aimed to assess patterns of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and to establish long-term surveillance protocols for late HCC recurrence.Material/MethodsThe 232 LT recipients experiencing subsequent HCC recurrence were categorized as Group 1, early recurrence (within 1 year of LT; n=117); Group 2, late recurrence (occurring in years 2–5; n=93); and Group 3, very late recurrence (after year 5; n=22).ResultsRecurrence was detected by only elevated tumor marker levels in 11.1%, 30.1%, and 45.5% of patients in Groups 1, 2, and 3, respectively (p<0.001). The proportion of intrahepatic and extrahepatic metastases was similar in all 3 groups. Common sites of extrahepatic metastasis were the lung and bone; these were also similar across the 3 groups. Overall post-recurrence patient survival rates were 60.2% at 1 year, 28.2% at 3 years, 20.5% at 5 years, and 7.0% at 10 years. Median post-recurrence survival periods were 10.2, 23.8, and 37.0 months in Groups 1, 2, and 3, respectively.ConclusionsWhile the pattern of HCC recurrence was similar regardless of time of recurrence, post-recurrence survival was significantly longer in patients with later recurrence. Long-term surveillance for HCC recurrence beyond 5 years after LT is recommended.

Late recurrence of hepatocellular carcinoma after liver transplantation.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and liver transplant (LT) prolongs survival. However, 15-20% will experience recurrent HCC, most occurring within 2 years of LT. HCC patients with late recurrences (>5 years after LT) may have distinctive clinical/biological characteristics. A retrospective review was conducted of 88 patients who underwent LT for HCC between 1993-2015, analyzing demographics, clinical factors, explant pathology, and outcome. Median follow-up was 6.4 years. HCC recurred in 15 (17.0%) patients with mean time to recurrence of 3.96 +/- 3.99 years. Five patients recurred >5 years post-LT. All late recurrences involved males in their 50s, recurring at 8.5 years on average. Recurrences occurred in chest wall (2), liver (2), lung (2), bone (1) and pelvis (1), with multifocal involvement in 2 patients. Four patients died within 18 months of late recurrence. The fifth patient is alive after ablation of liver recurrence and treatment with sorafenib and everolimus. One-third of post-LT patients with recurrent HCC experienced late recurrence. Although the sample size makes it difficult to identify significant risk factors, this study highlights the importance of long-term follow up and need for biomarkers to identify patients at risk for late recurrences.

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

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. 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, gamma-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. 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 recurrence. Patients with three or more risk factors were at significant higher risk of early recurrence. APRI>0.23 and positive hepatitis B e antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence. 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.

Prophylactic liver transplantation for high-risk recurrent hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Radical treatment of HCC in early stages results in a long disease-free period and improved overall survival. The choice of optimal management strategy for HCC mainly depends on the severity of the underlying liver disease. For patients with decompensated liver cirrhosis and HCC within Milan criteria (MC), liver transplant (LT) is the choice of treatment. However, for patients with good residual liver reserve and HCC within MC, selection of other curative treatments such as liver resection (LR) or radiofrequency ablation may be a reasonable alternative. For patients without cirrhosis, LR can result in an overall survival similar to that provided by LT. Therefore, it is an accepted alternative to LT especially in areas with organ shortage. However, the cumulative 5-year recurrence rate of HCC post LR might be as high as 70%. For initial transplant-eligible (within MC) patients with recurrent HCC post LR, salvage liver transplant (SLT) was first proposed in 2000. However, most patients with recurrent HCC considered for SLT are untransplantable cases due to HCC recurrence beyond MC or comorbidity. Thus, the strategy of opting for SLT results in the loss of the opportunity of LT for these patients. Some authors proposed the concept of “de principe liver transplant” (i.e., prophylactic LT before HCC recurrence) to prevent losing the chance of LT for these potential candidates. Factors associated with the failure of SLT will be dissected and discussed in three parts: Patient, tumor, and underlying liver disease. Regarding patient-related factors, the rate of transplantability depends on patient compliance. Patients without regular follow-up tend to develop HCC recurrence beyond MC at the time of tumor detection. Advancing age is another factor related to severe comorbidities when LT is considered for HCC recurrence, and these elderly candidates become ineligible as time goes by. Regarding tumor-related factors, histopathological features of the resected specimen are used mostly for determining the prognosis of early HCC recurrences. Such prognostic factors include the presence of microvascular invasion, poor tumor differentiation, the presence of microsatellites, the presence of multiple tumors, and the presence of the gene-expressing signature associated with aggressive HCC. These prognostic factors might be used as a selection tool for SLT or prophylactic LT, while remaining mindful of the fact that most of them are also prognostic factors for post-transplant HCC recurrence. Regarding underlying liver disease-related factors, progression of chronic viral hepatitis and high viral load may contribute to the development of late (de novo) HCC recurrence as a consequence of sustained inflammatory reaction. However, correlation between the severity of liver fibrosis and tumor recurrence is still controversial. Some prognostic scoring systems that integrate these three factors have been proposed to predict recurrence patterns after LR for HCC. Theoretically, after excluding patients with high risk of post-transplant HCC recurrence, either by observation of a cancer-free period or by measurement of biological factors (such as alpha fetoprotein), prophylactic LT following curative resection of HCC could be considered for selected patients with high risk of recurrence to provide longer survival.

Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection

BackgroundIntrahepatic recurrence is a significant problem for patients who have undergone a hepatic resection for hepatocellular carcinoma (HCC). The objective of the present study was to identify risk factors and evaluate the management of early and late recurrence of solitary HCC after curative resection. MethodsIncluded in this study were 816 patients with solitary HCC who underwent a curative partial hepatectomy. Intrahepatic recurrence in these patients was followed up retrospectively. Prognosis and therapy for the recurrence were investigated and analysed. ResultsEarly and late intrahepatic recurrence occurred in 423 patients and 199 patients, respectively. Multivariate analysis showed that a tumour diameter >5 cm, the absence of a tumour capsule and the presence of microvascular invasion were correlated with early recurrence, whereas cirrhosis and alphafetal protein >400 μg/l were independent risk factors contributing to late recurrence. The 5year survival of HCC patients with early recurrence was significantly lower than that of patients with late recurrence. Further curative treatment for intrahepatic recurrence offered a 5year overall survival of 56.0%, which was better than alternative management. ConclusionEarly and late recurrences of solitary HCC after curative resection are associated with different predictive factors. The time to recurrence and further curative treatment after recurrence were the best predictors of survival post recurrence.