Repeated transarterial chemoembolisation using different chemotherapeutic drug combinations followed by MR-guided laser-induced thermotherapy in patients with liver metastases of colorectal carcinoma

Background:

To evaluate a treatment protocol with repeated transarterial-chemoembolisation (TACE) downsizing before MR-guided laser-induced interstitial thermotherapy (LITT) using different chemotherapeutic combinations in patients with unresectable colorectal cancer (CRC) liver metastases.

Methods:

Two hundred and twenty-four patients were included in the current study. Transarterial-chemoembolisation (mean 3.4 sessions per patient) was performed as a downsizing treatment to meet the LITT requirements (number⩽5, diameter <5 cm). The intra-arterial protocol consisted of either Irinotecan and Mitomycin (n=77), Gemcitabine and Mitomycin (n=49) or Mitomycin alone (n=98) in addition to Lipiodol and Embocept in all patients. Post TACE, all patients underwent LITT (mean 2.2 sessions per patient).

Results:

Overall, TACE resulted in a mean reduction in diameter of the target lesions of 21.4%. The median time to progression was 8 months, calculated from the start of therapy and the median local tumour control rate was 7.5 months, calculated as of therapy completion. Median survival of patients calculated from the beginning of TACE was 23 months (range 4–110 months), in patients treated with Irinotecan and Mitomycin the median was 22.5 months, Gemcitabine and Mitomycin 23 months and Mitomycin only 24 months with a statistically significant difference between the groups (P<0.01).

Conclusion:

Repeated TACE offers adequate downsizing of CRC liver metastases to allow further treatment with LITT. The combined treatment illustrates substantial survival rates and high local tumour control with statistically significant differences between the three protocols used. Further randomised trials addressing the current study results are required.     

Multidisciplinary treatment of patients with hepatocellular carcinoma

Hepatocellular carcinoma is one of the most common malignancies in the world. When it is diagnosed, patients can choose from among several potentially curative treatments, such as surgical resection, transplantation, ablation therapy and transcatheter arterial chemoembolization. This review will give an overview of the present management of hepatocellular carcinoma. Liver transplantation is considered the best curative option, achieving a high rate of complete response, especially in patients with small hepatocellular carcinoma and good residual liver function. However, a shortage of donor livers restricts the availability of transplantation. In addition, only a minority of patients with hepatocellular carcinoma can be treated surgically, owing to impaired hepatic reserve, multiple intrahepatic lesions, extrahepatic lesions and the inability to obtain an optimal tumor-free margin. Therefore, for most patients, other types of interventions (transcatheter arterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation) have been developed. Among them, two local ablative modalities, percutaneous ethanol injection and percutaneous radiofrequency ablation, have been accepted as the only potentially curative nonsurgical treatments for hepatocellular carcinoma. Radiofrequency ablation may become a standard nonsurgical treatment option for patients with early hepatocellular carcinoma.     

Long-term survival and postoperative complications of pre-liver transplantation transarterial chemoembolisation in hepatocellular carcinoma: A systematic review and meta-analysis

ObjectivesThe aim of this meta-analysis was to conduct a contemporary systematic review of high quality non-randomised controlled trials to determine the effect of pre-liver transplantation (LT) transarterial chemoembolisation (TACE) on long-term survival and complications of hepatocellular carcinoma (HCC) patients.BackgroundTACE is used as a neoadjuvant therapy to mitigate waitlist drop-out for patients with HCC awaiting LT. Previous studies have conflicting conclusions on the effect of TACE on long-term survival and complications of HCC patients undergoing LT.MethodsCINAHL, Cochrane Controlled Register of Trials, Embase, PubMed, and Web of Science were systematically searched. Baseline characteristics included number of patients outside Milan criteria, tumour diameter, MELD score, and time on the waiting list. Primary outcomes included 3- and 5-year overall and disease-free survival. Secondary outcomes included tumour recurrence, 30-day postoperative mortality, and hepatic artery and biliary complications.ResultsTwenty-one high-quality NRCTs representing 8242 patients were included. Tumour diameter was significantly larger in TACE patients (3.49 cm vs 3.15 cm, P = 0.02) and time on the waiting list was significantly longer in TACE patients (4.87 months vs 3.46 months, P = 0.05), while MELD score was significantly higher in non-TACE patients (10.81 vs 12.35, P = 0.005). All primary and secondary outcomes displayed non-significant differences.ConclusionPatients treated with TACE had similar survival and postoperative outcomes to non-TACE patients, however, they had worse prognostic features compared to non-TACE patients. These findings strongly support the current US and European clinical practice guidelines that neoadjuvant TACE can be used for patients with longer expected waiting list times (specifically >6 months). Randomised controlled trials would be needed to increase the quality of evidence.     

原发性肝细胞癌R0切除术后肝外转移患者生存分析

目的分析原发性肝细胞癌(hepatocellular carcinoma,HCC)患者R0切除术后肝外转移的生存时间和影响因素。方法回顾性分析2001-01-2010-12青岛大学附属医院收治的597例行R0切除术的原发性HCC患者临床资料和随访结果。Logistic回归分析术后肝外转移复发较单纯肝内复发的独立危险因素;Kaplan-Meier(Log-rank检验)分析不同部位肝外转移患者的预后。结果肝内复发组中位生存时间18.0个月,显著长于肝外转移复发组的8.0个月,χ2=25.2,P<0.001。经Logistic回归分析,年龄>60岁(OR=2.555,P=0.003)、肿瘤直径>5cm(OR=2.094,P=0.027)、肿瘤亚临床破裂型(OR=6.407,P=0.010)和血管癌栓(OR=5.267,P=0.003)为发生肝外转移的独立危险因素。单因素分析显示,与肝内复发组比较,肝外转移组中肿瘤亚临床破裂型(χ2=8.261,P=0.004)、HBsAg或Anti-HCV阳性(χ2=6.011,P=0.014)、谷丙转氨酶≤60U/L(χ2=5.064,P=0.024)、肿瘤侵及肝被膜(χ2=11.778,P=0.001)的患者显著增多。Logistic回归分析显示,与单纯肝内复发相比,肿瘤亚临床破裂型(OR=3.298,P=0.008)、谷丙转氨酶≤60U/L(OR=2.022,P=0.024)、肿瘤侵及肝被膜(OR=2.636,P=0.003)是发生肝外转移的独立危险因素。肝外转移最常见的脏器为肺、腹腔、骨骼和肾上腺等,其中接受手术切除、射频消融和索拉非尼等治疗患者的复发后生存时间高于仅对症治疗者。结论患者高龄、肿瘤大小、血管癌栓和肿瘤亚临床破裂与肝癌切除术后肝外转移的发生密切相关;对术后发生肝外转移患者,早期发现和治疗可提高患者复发后生存时间。     

伽马刀治疗22例巨块型原发性肝癌临床观察

目的:分析伽马刀治疗巨块型原发性肝癌的疗效及预后因素。方法:2005年8月至2012年4月22例巨块型肝癌行伽马刀治疗,以40%-60%等剂量曲线为处方剂量线,中位剂量42Gy（范围30-50Gy）,3-5Gy/次, 9-13次完成。靶区为肝内病灶包括或不包括门脉癌栓。治疗后每1-3个月行血液和影像学检查（CT或MRI）。随访时间3-36个月,2013年9月结束。结果:总生存期3-36个月,中位生存期6.5个月,1-3年生存率分别为31.8%、22.7%、4.5%,有效率68.2%（CR 3例,PR 12例,SD 6例, PD 1例）。5例出现RTOG标准III级晚期放射性肝损伤。Kanplan-meier单因素分析显示AFP（P=0.002）、等效生物剂量（P=0.002）的生存差异有统计学意义（AFP＜1171ng/ml好于≥1171ng/ml,≥60Gy好于<60Gy）;COX多因素分析显示等效生物剂量是有意义的预后影响因素（P=0.009）。 结论:伽马刀治疗为巨块型肝癌可选方式之一,巨块型肝癌仍应给予足够剂量以改善肿瘤局控率和预后。     

小肝癌DNA含量分析

应用ＭＩＰＳ－１型自动图像分析仪，检测２５例小肝癌标本，探讨肿瘤细胞膜ＤＮＡ含量与小肝癌临床病理学关系，结果表明；肝癌细胞核ＤＮＡ含量与术前ＡＦＰ水平，肿瘤大小，有否包膜形成ｋａｎａｉ分型无关，在肿瘤细胞分化未成熟及复发组病例，ＤＮＡ含量明增高，提出核ＤＮＡ含量是反映肿瘤细胞生物学恶性程度的重要指标，可望成为独立的预后因子。     

Ⅲ期或Ⅳa1期肝癌肝移植的生活质量和生存率

目的 评价中期原发性肝癌(简称肝癌)肝移植的治疗效果,探讨更适合我国国情的肝癌肝移植标准.方法 以美国肝癌研究小组改良的TNM分期为基础,将肝癌分为早(Ⅰ期或Ⅱ期)、中(Ⅲ期或Ⅳa1期)、晚(Ⅳa2期或Ⅳb期)三期.用卡氏体能状况评分系统(Karnofsky performance status,KPS)作为生活质量评价工具,对我院2003年3月至2006年1月实施的中期肝癌肝移植分别于术前和术后评价其生活质量,记录术后无瘤存活时间和总存活时间,并计算不同时间点的无瘤生存率和总生存率.结果 中期肝癌患者术前生活质量属"低下"范畴,肝移植手术1周后生活质量逐步改善,3周时即显著优于术前(P=0.038),3个月和6个月时均有进一步改善.9个月时无瘤者生活质量即达到"良好"水平,与健康人相当,并在观察期结束时保持在这一高水平状态.术后1年、2年和3年生存率分别为91.0%、83.2%和80.0%,无瘤生存率分别为86.5%、81.9%和79.4%.结论 中期肝癌患者接受肝移植治疗能改善生活质量、延长生存时间,对中期肝癌可积极考虑肝移植治疗.     

Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Patients with unresectable hepatocellular carcinoma (HCC) have a dismal prognosis. The objective of this study was to evaluate whether patient-reported baseline quality of life (QoL) measured by the EORTC QLQ-C30 instrument is predictive of survival for these patients. MATERIALS AND METHODS: Two hundred and thirty-three patients with unresectable HCC (mainly hepatitis B-associated) who were recruited into two separate randomized phase III clinical studies, based on palliative chemotherapy and palliative hormonal therapy, respectively, gave consent and received pretreatment QoL assessment. EORTC QLQ-C30 scores and clinical variables at the time of study entry were analyzed to identify factors that influenced survival by applying multivariate analysis. Independent prognostic factors for survival were studied by Cox regression analysis. RESULTS: Median survival of the 233 patients was 5.5 months (95% CI 4.2-6.5 months). Significant independent predictors of shorter survival were advanced Okuda staging (P = 0.0030; HR = 2.058), high baseline total bilirubin (P = 0.0008; HR = 1.013) and worse QoL score in the appetite score domain (P = 0.0028; HR for 10 point increase = 1.070). Patients who were entered into the chemotherapy trial (P = 0.0002; HR = 0.503), those who scored better in the physical functioning domain (P = 0.0034; HR for 10 point decrease = 0.911) and the role functioning domain (P = 0.0383; HR for 10 point decrease = 0.944) of the QoL questionnaire, were associated with longer survival. CONCLUSIONS: In the studied HCC population, patient-reported baseline QoL provides additional prognostic information that supplements traditional clinical factors, and is a new prognostic marker for survival for patients with unresectable HCC.     

Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy.

BACKGROUND: Cancer patients who are hepatitis B virus (HBV) carriers and undergoing chemotherapy (CT) may be complicated by HBV reactivation. Over 80% of hepatocellular carcinoma (HCC) patients are HBV carriers; however, the incidence of HBV reactivation during CT has not been well-reported. A prospective study was conducted to determine the incidence of HBV reactivation, the associated morbidity and mortality, and possible risk factors. PATIENTS AND METHODS: 102 HBsAg-positive patients with inoperable HCC underwent systemic CT. Patients received either combination cisplatin, interferon, doxorubicin and fluorouracil (PIAF) or single-agent doxorubicin. They were followed up during and for 8 weeks after CT. RESULTS: In 102 patients, 59 (58%) developed hepatitis amongst whom 37 (36%) were attributable to HBV reactivation. Twelve (30%) died of HBV reactivation. CT was interrupted in 32 patients (86%) with reactivation and 54 (83%) without reactivation (P>0.05). The median survivals were 6.00 and 5.62 months, respectively (P=0.694). Elevated baseline alanine aminotransferase (ALT) was found to be a risk factor. CONCLUSION: HBV reactivation is a common cause of liver damage during CT in HBsAg-positive HCC patients. The only identifiable associated risk factor was elevated pre-treatment ALT. Further studies into the role of antiviral and novel anticancer therapies are required to improve the prognosis of these patients.     

Decreasing disparity in liver transplantation among white and Asian patients with hepatocellular carcinoma : California, 1998-2005

BACKGROUND.

A preliminary study using national cancer surveillance data from 1998 through 2002 suggested that there were significant differences between non‐Hispanic whites (‘whites’) and Asian/Pacific Islanders (APIs) in the use of liver transplantation as a treatment for hepatocellular carcinoma (HCC).

METHODS.

The objective of the current study was to examine whether differences in liver transplantation between whites and APIs with HCC were changing over time. By using a population‐based, statewide cancer registry, data were obtained on all HCC cases diagnosed in California between 1998 and 2005, and the study was limited to white and API patients with nonmetastatic HCC who had tumors that measured ≤5 cm in greatest dimension (n = 1728 patients).

RESULTS.

From 1998 through 2003 (n = 1051 patients), the odds of undergoing liver transplantation were 2.56 times greater for white patients than for API patients (95% confidence interval [CI], 1.72–3.80 times higher), even after adjusting for age, sex, marital status, year of diagnosis, TNM stage, and tumor grade. In contrast, during 2004 and 2005 (n = 677 patients), there were no significant differences in the odds of undergoing liver transplantation. Between 2002 and 2004, changes in liver transplantation policy assigned priority points to patients with HCC (initially to stage I and II, then to stage II only). After the policy changes, API patients with HCC experienced a significant increase in stage II diagnoses, whereas white patients did not.

CONCLUSIONS.

In California, there was a large and significant disparity in the rate of liver transplantation among white and API patients with HCC from 1998 through 2003 but not during 2004 and 2005. Changes in liver transplantation policy from 2002 through 2004 may have played a role in decreasing this difference. Cancer 2008. © 2008 American Cancer Society.     

Survival and intra-hepatic recurrences after laparoscopic radiofrequency of hepatocellular carcinoma in patients with liver cirrhosis

BACKGROUND: The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. Percutaneous radiofrequency interstitial thermal ablation proved to be effective, too. Our objective was to assess a novel operative combination of laparoscopic ultrasound (LUS) with laparoscopic radiofrequency (LRF) in the treatment of HCC not amenable to liver resection. METHODS: One hundred and four patients with HCC in liver cirrhosis were submitted to laparoscopic LRF. A LRF was indicated in patients not amenable to liver resection that had at least one of the following criteria: (a) severe impairment of the coagulation tests; (b) large tumors (but <5 cm) or multiple lesions requiring repeated punctures; (c) superficial lesions adjacent to visceral structures; (d) deep-sited lesions with a very difficult or impossible percutaneous approach; (e) short-term recurrence of HCC following percutaneous loco-regional therapies. RESULTS: The LRF procedure was completed in 102 out of 104 patients (98% feasibility rate). LUS identified 26 new malignant lesions (25%) undetected by pre-operative imaging. There was no operative mortality. Seventy-six patients had no complication (73%). At 1-month computed tomography (CT) evaluation, a complete response with a 100% necrosis was achieved in 88 out of 101 patients (87%). During the follow-up (mean follow-up: 22.5 +/- 15.9 months), 55 patients (54%) developed new malignant nodules (42% of these recurrences were localized in the same segment of the HCC treated). CONCLUSIONS: LRF of HCC proved to be a safe and effective technique at least in the short and mid-term: in fact it permits to treat lesions not treatable with the per cutaneous approach, to detect 25% of new HCC nodules and it has a low morbidity rate.     

符合米兰标准的老年肝癌肝移植受者的预后评价:一项基于SEER数据库的回顾性研究

目的:探讨符合米兰标准的老年（>65岁）肝癌肝移植受者的远期预后。方法:基于美国SEER数据库2004年至2015年间801例符合米兰标准的肝癌肝移植受者的临床数据,利用Kaplan-Meier法比较老年组（>65岁,94例）与青年组（18~65岁,707例）肝移植术后的总体生存率（overall survival,OS）和肝癌特异生存率（liver cancer specific survival,LCSS）。Cox比例风险模型用于分析影响肝癌肝移植受者预后的危险因素。结果:符合米兰标准的老年（66~75岁组、>75岁组）肝癌患者肝移植治疗占比（14.4%、0.2%）显著低于青年肝癌患者（30.3%）（P＜0.05）。肝癌肝移植受者的中位年龄逐年增加,其由2004年至2006年间的55.0岁渐增至2013年至2015年间的60.0岁（P＜0.05）。Kaplan-Meier分析提示青年组OS优于老年组（1、3、5、10年OS,93.5%、83.3%、77.9%、64.0% vs 91.2%、80.8%、66.4%、46.6%,P＜0.05）,但二者LCSS无异（1、3、5、10年LCSS,97.5%、91.9%、88.8%、82.7% vs 97.7 %、89.4%、78.1%、73.9%,P＞0.05）。多因素Cox回归分析提示受者年龄、肿瘤分化程度是影响肝癌肝移植受者OS的独立危险因素（均P＜0.05）,而肿瘤分化程度、微血管浸润则是影响肝癌肝移植受者LCSS的独立危险因素（均P＜0.05）。结论:受者年龄并不是肝癌肝移植远期预后的良好预测指标;经严格筛选的老年（>65岁）肝癌肝移植受者有机会获得与青年肝癌肝移植受者相近的预后。     

A randomised phase II study of TSU-68 in patients with hepatocellular carcinoma treated by transarterial chemoembolisation

BackgroundTSU-68 is an antitumour drug that acts by inhibiting angiogenesis. We evaluated the efficacy and safety of TSU-68 in combination with transarterial chemoembolisation (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC).Patients and MethodsIn this multicenter, open-label phase II study, we randomised patients with HCC who had been treated with a single session of TACE to receive either 200 mg TSU-68 twice daily or no medication. The primary end-point was progression-free survival (PFS).ResultsA total of 103 patients were enrolled. Median PFS was 157.0 days (95% confidence interval [CI], 124.0–230.0 days) in the TSU-68 group and 122.0 days (95% CI, 73.0–170.0 days) in the control group. The hazard ratio was 0.699 (95% CI, 0.450–1.088). Fatigue, elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, oedema and anorexia were more frequent in the TSU-68 group than in the control group. The most frequent grade 3/4 adverse events were AST elevation (46% of patients in the TSU-68 group and 12% of controls) and alanine aminotransferase elevation (26% of patients in the TSU-68 group and 8% of controls). Two deaths, grade 5 hepatic failure and melena were noted in the TSU-68 group.ConclusionThis exploratory study shows a trend towards prolonged PFS with TSU-68 treatment after a single session of TACE, but this observation was not statistically significant. The two deaths were related to the study treatment. These results suggest that further examination of the study design is necessary to determine whether TSU-68 has any clinical benefits when combined with TACE.     

Liver resection for hepatocellular carcinoma in patients who have undergone prior renal transplantation

BACKGROUND AND OBJECTIVES: Because renal transplantation recipients require immunosuppressive drugs, they have a higher incidence of subsequent malignancies. Among them, hepatocellular carcinoma (HCC) is common. Although liver resection remains an option for curing HCC, the role of liver resection in renal transplantation recipients remains unclear. METHODS: A retrospective review of liver resection for newly diagnosed HCC in 680 patients was conducted. Among them, 18 patients had undergone prior renal transplantation (RT group). The patient background, tumor characteristics, early and long-term results after liver resection were compared with the other 662 patients who had not previously undergone renal transplantation (non-RT group). RESULTS: The patient's background characteristics were comparable between RT and non-RT group. The tumor characteristics, postoperative morbidity, and mortality were not significantly different between the two groups. The 5-year disease-free survival rates in RT and non-RT groups were 18.8% and 41.2%, respectively (P = 0.242), whereas 5-year actuarial survival rates in RT and non-RT groups were 59.1% and 58.3%, respectively (P = 0.738). Two patients lost their graft kidney 3 and 8 years after liver resection. CONCLUSION: With careful protection of the graft kidney, liver resection is still a justified treatment option for HCC in patients who have undergone renal transplantation.     

Curative therapies for hepatocellular carcinoma: an update and perspectives

Curative treatments, including liver transplantation, surgical resection and percutaneous treatments, are the recommended therapies in BCLC-0 (Barcelona Clinic of Liver Cancer) or BCLC-A hepatocellular carcinoma (HCC). This review provides an overview of some issues of clinical importance concerning curative treatments in HCC.