Pre-operative predictors of post-hepatectomy recurrence of hepatocellular carcinoma: Can we predict earlier?

Backgrounds and purposeTo determine the predictors for recurrence in patients receiving curative hepatectomy for hepatocellular carcinoma (HCC).MethodsFrom January 2001 to July 2007, all patients having hepatectomy for first occurrence HCC with curative intent were identified from a prospectively collected database. Prognostic factors for recurrence and survival after resection were analyzed.ResultsA total of 235 patients were included. With a median follow-up of 50.2 (0.07–125.1) months, the recurrence rate was 57.0%. The 1-, 3-, and 5-year overall survival rates were 83.9%, 66.0%, and 58.1% respectively. Multivariate analysis demonstrated that multi-focal lesions (HR: 2.93, P < 0.001), alpha-fetoprotein (AFP) level greater than 100 ng/ml (HR: 1.74, P = 0.002) and history of tumor rupture (HR: 2.84, P = 0.003) were independent risk factors for recurrence of HCC after hepatectomy.ConclusionsPredictors for HCC recurrence can be identified before operation. These important parameters should be considered before and after contemplating curative resection for HCC patients and for risk stratification in future clinical trials for neoadjuvant or post-resection adjuvant therapy. The possible use of neoadjuvant or adjuvant treatment to improve survival should be addressed by further trials.     

Late recurrence of hepatocellular carcinoma after liver transplantation: is an active surveillance for recurrence needed?

Introduction

Liver transplantation (OLT) is considered the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rates, when restrictive selection criteria are applied. Nevertheless, tumor recurrence may occur in 3.5% to 21% of recipients. It usually occurs within 2 years following OLT, having a major negative impact on prognosis. The efficacy of active posttransplantation surveillance for recurrence has not been demonstrated, due to the poor prognosis of recipients with recurrences.

Aim

To analyze the clinical, pathological, and prognostic consequences of late recurrence (>5 years after OLT).

Method

We analyzed the clinical records of 165 HCC patients including 142 males of overall mean age of 58 ± 6.9 years who underwent OLT between July 1994 and August 2011.

Results

Overall survival was 84%, 76%, 66.8%, and 57% at 1, 3, 5, and 10 years, respectively. Tumor recurrence, which was observed in 18 (10.9%) recipients, was a major predictive factor for survival: its rates were 72.2%, 53.3%, 26.7%, and 10% at 1, 3, 5, and 10 years, respectively. HCC recurrence was detected in 77.8% of patients within the first 3 years after OLT. Three recipients (100% males, aged 54-60 years) showed late recurrences after 7, 9, and 10 years. In only one case were Milan criteria surpassed after the examination of explanted liver; no vascular invasion was detected in any case. Recurrence sites were peritoneal, intrahepatic, and subcutaneous abdominal wall tissue. In all cases, immunosuppression was switched from a calcineurin-inhibitor to a mammalian target of rapamycin inhibitor. We surgically resected the extrahepatic recurrences. The remaining recipient was treated with transarterial chemoembolization with doxorubicin-eluting beads and sorafenib. Prognosis after diagnosis of recurrence was poor with median a survival of 278 days (range, 114-704).

Conclusions

Global survival, recurrence rate, and pattern of recurrence were similar to previously reported data. Nevertheless, in three patients recurrence was diagnosed >5 years after OLT. Although recurrence was limited and surgically removed in two cases, disease-free survival was poor. Thus, prolonged active surveillance for HCC recurrence beyond 5 years after OLT may be not useful to provide a survival benefit for these patients.     

Does graft hemodynamics affect the risk of hepatocellular carcinoma recurrence after liver transplantation?

Although experimental studies have reported that hepatic ischemia-reperfusion injury promotes tumor growth and metastases, the impact of graft hemodynamics on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is unclear. To investigate the association between graft hemodynamics and HCC recurrence after LT, we conducted a retrospective analysis of 279 patients who underwent LT for HCC. Graft hemodynamics including portal vein flow (PVF), hepatic artery flow (HAF), and total hepatic flow (THF) was analyzed as a predictor of HCC recurrence, using competing risk regression analyses. The cutoff values of PVF, HAF, and THF were set at the lower quartile of distribution. A cumulative recurrence curve demonstrated that low THF (<1511 mL/min, P = .005) was significantly associated with increased recurrence, whereas neither low PVF (<1230 mL/min, P = .150) nor low HAF (<164 mL/min, P = .110) was significant. On multivariate analysis, outside Milan criteria (sub-hazard ratio [SHR] = 3.742; P < .001), microvascular invasion (SHR = 3.698; P < .001), and low THF (SHR = 2.359; P = .010) were independently associated with increased HCC recurrence. In conclusion, our findings suggest that graft hemodynamics may play an important role in HCC recurrence after LT.     

Can biological markers predict recurrence and progression of superficial bladder cancer?

Biological markers that are predictive of recurrence and progression of superficial bladder tumors must provide additional information to that provided by multiplicity, size and grade. Field anomalies in normal appearing urothelium of patients with papillary superficial transitional cell carcinoma have been associated with tumor antigens and chromosome 9 deletions. Also, primary tumors with chromosome 9 deletions are associated with a higher risk of recurrence. Abnormal expression of p53, p21 and Ki-67 cell cycle markers have little predictive value for recurrence. However, p53 overexpression or mutation and decreased expression of p27 are associated with cancer progression and survival. New markers, such as mutations in the fibroblast growth factor receptor 3 gene (found in 30% of tumors), anomalies of the PTEN gene and vascular endothelial growth factor expression, may have potential and require further evaluation. Molecular fingerprints of superficial tumors with distinct clinical behavior are being rapidly unravelled. Large-scale clinical studies are urgently needed to provide supportive evidence for their incorporation in clinical management.     

Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression?

BACKGROUND: Liver transplantation is currently offered to a limited number of patients with hepatocellular carcinoma (HCC) because of strict criteria introduced in the past to avoid recurrence. Immunosuppression represents a risk factor for tumor growth; the schedules of the immunosuppressant drugs have been modified through the years, aiming to reduce their dosage to the effective minimum. METHODS: A series of 106 consecutive patients with HCC who underwent transplantation over a 15-year period at a single institution was retrospectively reviewed to ascertain whether tumor recurrence was influenced by the Milano criteria presently adopted in patient selection and whether the dosage of immunosuppressant agents administered was associated with tumor recurrence. Fifteen patients who died postoperatively and 9 with a follow-up of less than 1 year were excluded; presence of the Milano criteria, tumor-node-metastasis staging, and the cumulative dosage of the single immunosuppressants given at different intervals in the first postoperative year were analyzed in the remaining 82 patients. The influence of these variables on overall and recurrence-free survival was assessed statistically. RESULTS: The Milano criteria did not influence recurrence-free survival, which was instead associated with the cumulative dosage of cyclosporine administered in the first postoperative year (93% 5-year recurrence-free survival for patients given low dosage vs. 76% for those given high dosage; P=0.01); T3 and T4 tumors did worse than T1 and T2 tumors. CONCLUSIONS: Current limits to transplantation for HCC might be reassessed in view of modified patient management; immunosuppression should be minimized in these patients.     

Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma?

BACKGROUND: Transarterial chemoembolization (TACE) before liver transplantation (LT) for hepatocellular carcinoma (HCC) has been proposed to prevent tumor progression, thus decreasing tumor recurrence and increasing survival. METHODS: We studied 46 patients undergoing LT for HCC who were divided in 2 groups--group A with pretransplant TACE (18 patients [39.1%]) and group B without pretransplant TACE (28 patients [60.9%])--and compared postoperative and long-term results between the 2 groups. RESULTS: There were no statistical differences in morbidity, transfusion needles, and postoperative time between-and no acute arterial or portal complication in-the 2 groups. There were no statistical differences in tumor recurrence (16.7 % vs 36.4 %, P=.16) with regard to pathway (mainly extrahepatic) or time. In group A patients, mean survival was 89.3+/-21.7 months with 1-, 3-, and 5-year actuarial survival rates of 83.3%, 60.5%, and 60.5%, respectively. In group B patients, mean survival was 75.1+/-19.1 months with 1-, 3-, and 5-year actuarial survival rates of 77.2%, 58.7%, and 38.1%, respectively. The differences in mean survival were not statistically significant (PX .56), nor was 5-year disease-free survival, which was 54% in group A and 39.5% in group B (P=.8). CONCLUSIONS: TACE is a safe procedure for candidates on the wait list who are scheduled for LT to treat HCC. Although TACE does not correlate with increased intraoperative difficulties or postoperative complications, it does not significantly improve tumor recurrence and survival.     

Can combination of osteopontin and peritumor-infiltrating macrophages be a prognostic marker of early-stage hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is one of the most frequent malignancy worldwide. The increasing incidence of HCC in the worldwide has sparked an emerging interest in prognostic markers of HCC. Osteopontin (OPN) is a secreted phosphoprotein which has been associated with progression and metastasis of HCC. Also, peritumoral macrophage (PTM) have been reported to facilitate tumor progression and metastasis. Recently, one study reported that combination of OPN with PTM may predict the prognosis of HCC after curative resection. The authors successfully identified that combination of these two markers is an independent predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. These findings might support the possibility that combination of OPN and PTM levels can be a prognostic tool. However, further investigations should be conducted before tumor OPN combined with PTMs can be accepted as a valid prognostic marker in clinical practice.     

Are autologous bone marrow stem cell transplantation and transcatheter arterial embolization the best choices for patients with hepatocellular carcinoma and hepatic dysfunction? Report of a case

The purpose of this work was to evaluate the effects of autologous bone marrow stem cell transplantation (AMSCT) and transarterial embolization (TAE) in patients with hepatocellular carcinoma (HCC) and hepatic dysfunction. A 58-year-old male with HCC and hepatic function of Child’s class C was treated with 8?ml of a lipiodol emulsion by injection into the artery feeding of his tumor, and >10⁸ bone marrow stem cells were isolated from 400?ml bone marrow and then injected into the right hepatic artery. The patient’s laboratory examinations revealed a progressive decrease in total bilirubin (from 264.8 to 77.9?μmol/L) and direct bilirubin (from 222.0 to 59.7?μmol/L) after 1?month, and a repeat CT showed that most of the tumor was filled with lipiodol. The combined treatment using AMSCT and TAE is a good choice of treatment for HCC patients who are unable to tolerate TACE due to hepatic dysfunction.     

Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation?

Background

There are scarce data on the use of sorafenib for the treatment of recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT).

Patients and Methods

Ten patients were treated with sorafenib after OLT following the Italian Drug Agency guidelines: they had well-compensated liver function (Child-Pugh class A in the case of cirrhosis), intermediate-or advanced-stage HCC, good general condition (performance status 0), and not suitable for loco-regional therapies. Patients with HCC recurrence after OLT were treated with sorafenib (400 mg twice daily). Adverse events (AEs) were assessed using National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI-CTCAE) v3.0 with tumor responses evaluated acording to modified Response Evaluation Criteria in Select Tumors) criteria.

Results

Median duration of treatment was 10 months (range, 2-18). Seven patients (70%) received an additionally targeted therapy with mTOR inhibitors as part of their immunosuppressive regimen. Most common grade 3 AEs included diarrhea (50%), hand-foot skin reaction (30%), and fatigue (20%). Sorafenib had to be discontinued in 3 patients (30%) due to AEs and 4 additional patients (40%) required a dose adjustment. No deterioration of liver graft function occurred. Three patients (30%) stopped treatment due to radiological progression of HCC, whereas 3 are still using the drug. Median time to progression was 8 months (range, 2-16). Median survival from start of therapy was 18 months (range, 4- 36).

Conclusion

Our preliminary results suggest that sorafenib is a safe effective therapy for recurrent HCC after OLT.     

Recurrence of hepatocellular carcinoma after living donor liver transplantation: what is the current optimal approach to prevent recurrence?

Background  

Liver transplantation plays an important role in the multimodal treatment options for patients with hepatocellular carcinoma (HCC). However, there has been little information about the prognosis for HCC recurrence after living donor liver transplantation (LDLT).