肝移植术后肝癌复发防治进展

肝移植是根治性治疗肝癌的方法之一,但肝移植术后肝癌复发严重影响移植患者的长期生存。通过积极的预防措施,免疫抑制剂调整,早期发现以及全面制订肝癌复发后的干预措施,有助于提高肝癌肝移植患者临床疗效并改善长期生存。为了进一步改善肝移植患者预后,从预防复发及复发后的治疗两大方面对肝移植术后肝癌复发的最新防治进展进行归纳和总结。     

Hepatocellular carcinoma: surgical treatment and prognostic variables in 56 patients

BACKGROUND/AIMS: Partial hepatectomy (PH) or total hepatectomy and orthotopic liver transplantation (OLT) may be curative in selected patients treated for hepatocellular carcinoma (HCC). The analysis of clinical series may help in the choice of the more appropriate treatment. METHODOLOGY: During the past 11 years, 40 patients with HCC were treated by PH and 16 patients underwent total hepatectomy and OLT. Selection criteria for transplantation were the liver function and the tumor resectability. RESULTS: The actuarial 1-, 3- and 5-year survival rates were 67%, 34% and 18%, respectively, after PH and 62%, 54% and 54% after OLT. The only prognostic factor after PH was the tumor extension to a single or both lobes. Patients with associated cirrhosis had significantly more post-operative complications, but a comparable long-term survival. The proliferative cell nuclear antigen labeling index (PCNA-LI), evaluated on tumoral tissue in 16 patients, showed that an index <30% indicates a better prognosis for HCC developing in non-cirrhotic liver. CONCLUSIONS: For patients carefully pre-operatively evaluated, the presence of an associated cirrhosis does not seem to modify the long-term survival after PH, and OLT may offer more than 50% 5-year survival. A PCNA-LI <30% appears to be a good prognostic factor in patients without cirrhosis.     

Hepatocellular cancer: Resection or transplantation

Surgery remains the treatment of choice for hepatocellular carcinoma (HCC). For HCC without underlying cirrhosis resection remains the mainstay treatment option. Prognosis depends on the stage of the tumor. Survival appears to be better for small (less than 5 cm) solitary tumors with negative resection margins and absence of vascular invasion. At present, liver transplantation does not have an established role in the treatment of HCC in a non-cirrhotic liver. Because of the high recurrence rate, it should not be considered for more advanced disease which is not amenable to resection. The surgical approach in cirrhotics depends not only on the stage of the tumor but also on the liver functional reserve. Tumor size, presence of multifocal disease, and vascular invasion determine the risk of HCC recurrence after resection, and the functional stability of the liver determines both resectability and outcome. In societies in which transplantation is not available, small tumors will be treated with liver resection. The outcome in patients with well preserved liver function is relatively good, at least in the medium term. However, recurrent tumor and progressive hepatic decompensation have significant adverse effects on long-term survival. Poor functional reserve may be associated with significant perioperative mortality and lower survival due to progressive liver failure. In our opinion, for small cirrhosis-related HCCs, liver transplantation offers better long-term prospects than resection. Therefore, if liver transplantation is available as an option it should be considered as the treatment of choice, particularly for younger patients with otherwise good life expectancy.     

Role of hepatectomy for recurrent or initially unresectable hepatocellular carcinoma

As a result of donor shortage and high postoperative morbidity and mortality after liver transplantation,hepatectomy is the most widely applicable and reliable option for curative treatment of hepatocellular carcinoma(HCC).Because intrahepatic tumor recurrence is frequent after loco-regional therapy,repeated treatments are advocated provided background liver function is maintained.Among treatments including local ablation and transarterial chemoembolization,hepatectomy provides the best long-term outcomes,but studies comparing hepatectomy with other nonsurgical treatments require careful review for selection bias.In patients with initially unresectable HCC,transarterial chemo-or radio-embolization,and/or systemic chemotherapy can down-stage the tumor and conversion to resectable HCC is achieved in approximately 20%of patients.However,complete response is rare,and salvage hepatectomy is essential to help prolong patients’survival.To counter the short recurrence-free survival,excellent overall survival is obtained by combining and repeating different treatments.It is important to recognize hepatectomy as a complement,rather than a contraindication,to other nonsurgical treatments in a mul-tidisciplinary approach for patients with HCC,including recurrent or unresectable tumors.     

Treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and is the third highest cause of cancer-related mortality. HCC usually develops in patients with chronic liver disease, particularly in those who also have cirrhosis. The possibility of curative treatment depends on both the stage of tumor and liver function. Effective treatments for HCC include percutaneous ablation, surgical resection, and liver transplantation. Both percutaneous ablation and surgical resection provide a high rate of complete responses and are assumed to improve survival that should exceed 50% at 5 years. Liver transplantation results in a better survival rate, and is not contraindicated by advanced liver dysfunction. However, its application is limited by the scarcity of donor organs. Treatments for advanced HCC include transarterial chemoembolization and chemotherapy. Although short-term prognosis of HCC patients has improved recently due to advances in early diagnosis and treatment, long-term prognosis is as yet far from satisfactory due to frequent recurrence. Prevention of recurrence of HCC remains one of the most challenging tasks in current hepatology.     

Patterns,treatments, and prognosis of tumor recurrence after resection for hepatocellular carcinoma with microvascular invasion: a multicenter study from China

BackgroundMicrovascular invasion (MVI) is a risk factor of post-hepatectomy tumor recurrence for hepatocellular carcinoma (HCC). The patterns, treatments, and prognosis have not been documented in HCC patients with MVI.MethodsA multicenter database of patients with HCC and MVI following resection was analyzed. The clinicopathological and initial operative data, timing and first sites of recurrence, recurrence management, and long-term survival outcomes were analyzed.ResultsOf 1517 patients included, the median follow-up was 39.7 months. Tumor recurrence occurred in 928 patients, with 49% within 6 months of hepatectomy and 60% only in the liver. The incidence of intrahepatic only recurrence gradually increased with time after 6 months. Patients who developed recurrence within 6 months of hepatectomy had worse survival outcomes than those who developed recurrence later. Patients who developed intrahepatic only recurrence had better prognosis than those with either extrahepatic only recurrence or those with intra- and extrahepatic recurrence. Repeat resection of recurrence with curative intent resulted in better outcomes than other treatment modalities.ConclusionPost-hepatectomy tumor recurrence in patients with HCC and MVI had unique characteristics and recurrence patterns. Early detection of tumor recurrence and repeat liver resection with curative intent resulted in improved long-term survival outcomes.     

Surgical treatment of intra hepatic recurrence of hepatocellular carcinoma

Recurrence after hepatocellular carcinoma(HCC) is frequent.Currently,there are no recommendations on therapeutic strategy after recurrence of HCC.Whereas the 5 year-recurrence rate after resection of HCC is 100%,this drops to 15% after primary liver transplantation.Repeat hepatectomy and salvage liver transplantation(SLT) could be performed in selected patients to treat recurrent HCC and enable prolonged overall survival after treatment of recurrence.Other therapies such as local ablation,chemoembolization or sorafenib could be proposed to those patients unable to benefit from resection or SLT.A clear definition of the place of SLT and "prophylactic" liver transplantation is required.Indeed,identifying risks factors for recurrence at time of primary liver resection of HCC may help to avoid recurrence beyond Milan criteria and non-resectable situations.In this review,we summarize the recent data available in the literature on the feasibility and outcomes of repeat hepatectomy and SLT as treatment for recurrent HCC.     

Use of transcatheter arterial infusion of anticancer agents with lipiodol to prevent recurrence of hepatocellular carcinoma after hepatic resection.

BACKGROUND/AIMS: Hepatectomy has been accepted as a reliable cure for primary hepatocellular carcinoma (HCC). However, the residual liver recurrence rate after hepatectomy remains high. To improve the prognosis after hepatectomy for HCC, repeated post-operative transcatheter arterial infusions of anticancer drugs and lipiodol (TAI) was given. This study evaluates the efficacy of this treatment for preventing residual liver recurrence after hepatectomy. METHODOLOGY: TAI after hepatectomy was performed in 24 (TAI group) of 65 cases showing tumor invasion such as infiltration to the capsule, intraportal spread, and intrahepatic metastasis. In TAI, a mixture of Mitomycin C (MMC) and Adriamycin (ADM) is administered with lipiodol via the hepatic artery. The recurrence and survival rates of the TAI (n = 24) and non-TAI (n = 41) groups were compared to evaluate the efficacy of TAI after hepatectomy. RESULTS: The TAI group had a lower cumulative residual liver recurrence rate than the non-TAI group (p < 0.01). Division of residual liver recurrence cases into two groups according to the duration of recurrence showed that the rate of recurrence within 1 year after hepatectomy was lower in the TAI group (10.0%) (1/10) than in the non-TAI group (48.4%) (15/31) (p = 0.07). Also, the cumulative survival rate in the TAI group was significantly higher (p < 0.05). The morbidity rate was 16.6%. Bilomas occurred without infection in 2 cases, and liver abscess in one. CONCLUSIONS: TAI may be an effective surgical adjuvant against residual liver recurrence, and we suggest that its effectiveness results from suppression of intrahepatic micrometastases rather than multicentric carcinogenesis.     

Salvage liver transplantation in the treatment of hepatocellular carcinoma: a meta-analysis

AIM: To evaluate survival and recurrence after salvage liver transplantation (SLT) for the treatment of hepatocellular carcinoma (HCC) compared with primary liver transplantation (PLT) using a meta-analysis.METHODS: Literature on SLT versus PLT for the treatment of HCC published between 1966 and July 2011 was retrieved. A meta-analysis was conducted to estimate pooled survival and disease-free rates. A fixed or random-effect model was established to collect the data.RESULTS: The differences in overall survival and disease-free survival rates at 1-year, 3-year and 5-year survival rates were not statistically significant between SLT group and PLT group (P > 0.05). After stratifying the various studies by donor source and Milan criteria, we found that: (1) Living donor liver transplantation recipients had significantly higher 1-year survival rate, lower 3-year and 5-year survival rates compared with deceased-donor liver transplantation (DDLT) recipients. And in DDLT recipients they had better 1-year and 5-year disease-free survival rate in SLT group; and (2) No difference was seen in 1-year, 3-year and 5-year survival rates between two groups who beyond Milan criteria at the time of liver transplantation.CONCLUSION: SLT can be effectively performed for patients with recurrence or deterioration of liver function after hepatectomy for HCC. It does not increase the perioperative mortality and has a similar long-term survival rates compared to PLT.     

Repeat hepatectomy is the most useful treatment for recurrent hepatocellular carcinoma

Hepatic resection has been regarded as a curative treatment for primary hepatocellular carcinoma (HCC), but a high incidence of postoperative recurrence is general. Thus it is important to predict the patterns of recurrence and select the appropriate treatment for recurrence for a better long‐term prognosis of patients with HCC. Clinicopathological studies on 80 patients with intrahepatic recurrence after curative hepatectomy suggested that nodular‐type recurrence with up to three nodules is mainly due to metachronous multicentric hepatocarcinogenesis rather than intrahepatic metastases. We reviewed 300 patients with recurrent HCC, and repeat hepatectomy was done in 78 cases (26.0%). The 3‐ and 5‐year survival rates after repeat hepatectomy were 82.8% and 47.5%, respectively, showing better prognosis than those for other treatments. Repeat hepatectomy is the preferred treatment offering a hope of long‐term survival for patients with recurrent HCC as long as liver function is sufficient; thus early detection of recurrence should be ensured.     

Current status and prospect of treatments for recurrent hepatocellular carcinoma

Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.     

Liver transplantation for solitary hepatocellular carcinoma less than 3 cm in diameter in Child A cirrhosis

Liver transplantation for hepatocellular carcinoma (HCC) is the treatment of choice for patients with unresectable tumors within the Milan criteria associated with Child B or C cirrhosis. Liver transplantation provides the best cure for both the HCC and the underlying cirrhosis. In recent years, some authors have advocated liver transplantation even for resectable early HCC associated with Child A cirrhosis, leading to a controversy of whether resection or transplantation should be the first-line therapy for patients with small HCC in Child A cirrhosis. Recent studies comparing liver resection and transplantation for early HCC demonstrated similar long-term survival of 60-70%, but liver transplantation is associated with a lower tumor recurrence rate. However, the current shortage of deceased donor liver grafts limits the applicability of liver transplantation for HCC. The use of live donor liver transplantation for patients with a small solitary HCC in Child A cirrhosis that is resectable may not be justified ethically because of the potential risk to the donors. Patients put on a transplantation waiting list run a significant risk of tumor progression and dropout, while liver resection is immediately applicable to all. Advocating primary liver transplantation for patients with early HCC associated with compensated cirrhosis will increase the waiting time for transplantation and further increases the chance of dropout. Resection first and salvage transplantation for recurrent tumors or liver failure is an alternative strategy that may reduce the use of liver grafts. However, the long-term survival result of such a strategy compared with primary liver transplantation remains unclear.     

Repeat hepatectomy for recurrent hepatic metastases from colorectal cancer.

BACKGROUND/AIMS: Resection of liver metastases from colorectal cancer is accepted as a safe, and curative treatment. Furthermore, repeat hepatectomy has been indicated for hepatic recurrence after initial hepatectomy to achieve long-term survival or cure. The present study is a retrospective review of our results using repeat hepatectomy for colorectal liver metastases to identify outcomes and prognostic factors associated with long-term survival. METHODOLOGY: Ninety-four patients underwent an initial hepatectomy for colorectal metastases between 1990 and 1995. Thirty patients had hepatic recurrence after the initial hepatectomy. Eleven patients underwent repeat hepatectomy for isolated hepatic recurrence. RESULTS: The operative mortality was 0%. The overall 5-year survival rate after detection of second liver metastases of 11 patients was 45.5%. The distribution of first liver metastases and disease-free interval between the first and second hepatectomy demonstrated significance in relation to survival after repeat hepatectomy (P = 0.0303 and 0.0338). CONCLUSIONS: Repeat hepatectomy for recurrent liver metastases from colorectal cancer was the most effective treatment to improve survival time for selected patients. In patients with isolated second liver metastasis, unilateral spread of first liver metastases, and a disease-free interval between the first and second hepatectomies of more than 12 months, long-term survival or cure can be expected after repeat hepatectomy.     

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.     

Prognostic value of γ-glutamyl transpeptidase to albumin ratio combined with aspartate aminotransferase to lymphocyte ratio in patients with hepatocellular carcinoma after hepatectomy

Hepatocellular carcinoma (HCC) is a malignant tumor associated with a high recurrence rate after hepatectomy. Recently, preoperative inflammatory and liver function reserve indices were found to predict increased risk of recurrence and decreased survival in HCC patients. This study aims to evaluate the ability of the γ-glutamyl transpeptidase-to-albumin ratio (GAR) and aspartate aminotransferase-to-lymphocyte ratio (ALRI), individually and in combination, to predict the prognosis of HCC patients after hepatectomy.We retrospectively reviewed 206 HCC patients who underwent radical resection at the General Hospital of Ningxia Medical University from January 2011 to November 2016. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off value for GAR and ALRI. The Pearson Chi-Squared test was used to analyze the correlations between GAR, ALRI and clinicopathological characteristics. Univariate and multivariate analyses were used to determine the predictive value of these factors for disease-free survival (DFS) and overall survival (OS). Survival rates were drawn according to the Kaplan-Meier method and differences between subgroups were compared by the log-rank statistics.GAR and ALRI were significantly correlated with gender, history of smoking, prothrombin time, tumor diameter, T stage and early intrahepatic recurrence by the Pearson Chi-Squared test (all P < .05). Univariate analysis indicated that T stage, GAR and ALRI were significantly correlated with DFS and OS in HCC patients after hepatectomy. Multivariate analysis illustrated that GAR and ALRI were independently related to DFS and OS in HCC patients. Preoperative GAR > 0.946 or ALRI > 18.734 predicted poor prognosis in HCC patients after hepatectomy. Additionally, the predictive scope of GAR combined with ALRI was more sensitive than that of either individual measurement alone.Our data indicate that there is a close association between the clinicopathological characteristics in HCC patients and increased GAR or ALRI. Higher levels of GAR and ALRI could sensitively and specifically predict a poor prognosis in HCC patients after hepatectomy. Furthermore, combined usage of GAR and ALRI could improve the accuracy of this prediction.     

Targeting of circulating hepatocellular carcinoma cells to prevent postoperative recurrence and metastasis

Currently,the main treatment for hepatocellular carcinoma(HCC)involves the surgical removal of tumors or liver transplantation.However,these treatments are often not completely curative,as they are associated with a risk for postoperative recurrence and metastasis.Circulating tumor cells(CTCs)are increasingly recognized as the main source for recurrence and metastasis after radical hepatectomies are performed.Many studies have demonstrated the association between the presence of either pre-or postoperative CTCs and an increased risk for HCC recurrence.To improve the therapeutic outcome of HCC,a personalized,comprehensive and multidisciplinary approach should be considered,involving the application of appropriate diagnostic and therapeutic measures targeting HCC CTCs in different stages throughout the course of treatment.This article proposes some HCC CTC-based strategies for the treatment of HCC,including the monitoring of HCC CTCs before,during and after radical hepatectomy,therapeutic targeting of HCC CTCs,prevention of the generation and colonization of CTCs,as well as the use of CTC indexes for the selection of indications,prediction of prognoses,and planning of individualized therapeutic regimens.Innovation and technological development of therapies targeting CTCs,as well as their translation into clinical practice,will help to effectively reduce postoperative recurrence and metastasis,and significantly prolong the survival of HCC patients.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

原发性肝癌外科治疗的理性思考

全球肝细胞癌（hepatocellular carcinoma,HCC）的发病率一直呈上升趋势,肝切除仍然是HCC患者的首选治疗。有临床症状肝癌患者的可切除率为20％～30％。大型肝切除术不输血是肝切除术的一个进展。原位肝移植应遵照米兰标准执行,并应把肝移植数量控制在肝切除数量的10％以下。HCC的微创治疗,包括经皮射频消融、经皮微波凝固治疗、冷冻治疗、高强度聚焦超声热疔等,一直在临床应用。芮静安提出的“120”肝外科技术适用于城市和农村的医院。未来,HCC患者治疗后的无瘤生存率将会提高。     

Preventive effect of regional radiotherapy with phosphorus-32 glass microspheres in hepatocellular carcinoma recurrence after hepatectomy

AIM： To evaluate the preventive effects of phosph- orus-32 glass microspheres （P32-GMS） in the recurrence of massive hepatocellular carcinomas （HCCs） after tumor resection. METHODS： Twenty-nine patients with massive HCCs received local P^32-GMS implantation after liver tumors were removed, while the other 38 patients with massive HCCs were not treated with P^32-GMS after hepatectomies. The radioactivity of the blood, urine and liver were examined. The complications, HCC recurrence and overall survival rates in the patients were analyzed. RESULTS： P^32-GMS implanted in the liver did not cause systemic absorption of p^32. There were no significant differences of postoperative complications between the patients with and without P^32-GMS treatment. The shortterm （six months and 1 year） and long-term （2, 3 and over 3 years） recurrence rates in patients who received P^32-GMS radiotherapy were significantly decreased, and the overall survival rates in this group were significantly improved. CONCLUSION： P^32-GMS implantation in the liver can significantly decrease the postoperative recurrence and improve the overall survival in HCCs patients after hepatectomy. This therapy may provide an innovative method in prevention of HCC recurrence after operation.     

Complete response to sorafenib in a patient with recurrent hepatocellular carcinoma

Partial hepatectomy is still the treatment of choice aiming at a cure for patients with hepatocellular carcinoma (HCC), provided that the patient can tolerate the treatment. For patients with multiple recurrent HCC after partial hepatectomy which cannot be treated by re-hepatectomy or local ablative therapy, the prognosis is extremely poor. Sorafenib is a molecular-targeted agent which has been demonstrated in two global phase III randomized controlled trials to show survival benefit for advanced HCC. Here, we present a 56-year-old patient with HCC who showed complete clinical response after sorafenib was used for tumor recurrence which developed 3 mo after partial hepatectomy. There was no evidence of progression of disease for 60 mo till now after continuous treatment with sorafenib.