Change in arterial tumor perfusion is an early biomarker of lenvatinib efficacy in patients with unresectable hepatocellular carcinoma

BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve(TIC) of arterial phase on contrastenhanced ultrasound(CEUS) as early imaging biomarkers of lenvatinib efficacy.AIM To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC.METHODS We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors(m RECIST). CEUS was performed at baseline before treatment(Day 0) and on day 7(Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in(Slope),time to peak(TTP) intensity, and the total area under the curve(AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on m RECIST.RESULTS The rate of change for all TIC parameters showed significant differences between the responders(n = 9) and non-responders(n = 11)(Slope, P = 0.025; TTP, P =0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and0.939, respectively.CONCLUSION CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.     

Assessment of lenvatinib treatment for unresectable hepatocellular carcinoma with liver cirrhosis

BackgroundThe present study aimed to assess the clinical features of patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC).MethodsThe clinical characteristics, adverse events, and radiological responses were evaluated for 51 consecutive patients.ResultsOf the study subjects, 37 patients had Child–Pugh class A (CPA) liver function, and 14 patients had Child–Pugh class B (CPB) liver function. The overall response rates in the CPA and CPB groups were 42.9% and 25.0%, respectively, and disease control rates were 82.9% and 83.3%, respectively, without significant difference (p = 0.2621 and 0.9697). There was no significant difference between CPA and CPB groups regarding the incidence of adverse events, except for hepatic coma. No significant difference was observed in the relative dose intensity between the CPA and CPB groups, for the first month, 1–2 months, or 2–3 months (p = 0.2368, 0.9368, and 0.9293).ConclusionThe comparable outcomes between the CPA and CPB groups suggest the acceptability of lenvatinib treatment in patients with impaired liver function, at least in the acute phase. With careful follow-up, the dose can be relatively intensified, even in patients with impaired liver function and this may contribute to offering comparable treatment.     

仑伐替尼治疗酪氨酸激酶抑制剂经治不可切除肝细胞癌患者的效果及安全性观察

目的 探索仑伐替尼在酪氨酸激酶抑制剂（TKI）经治不可切除肝细胞癌（HCC）患者中的疗效和安全性。方法 收集2019年1月—2020年1月就诊于首都医科大学附属北京地坛医院接受仑伐替尼治疗的76例不可切除HCC患者临床资料,根据治疗方式分为TKI初治组（n=49）和TKI经治组（n=27）。研究观察至入组后1年或调整治疗方案或肿瘤进展或死亡。比较两组无进展生存期（PFS）、客观缓解率（ORR）、疾病控制率（DCR）、不良事件发生率等。计量资料两组间比较采用t检验或Wilcoxon秩和检验。计数资料组间比较用χ²检验或Wilcoxon秩和检验。应用Kaplan-Meier法进行生存分析,组间比较采用log-rank检验。结果 TKI初治组和TKI经治组中位PFS（115 d vs 72 d,P=0.148）、ORR（36.7%vs 18.5%,P=0.098）、DCR（65.3%vs 55.6%,P=0.402）、3级及以上不良事件发生率（24.5%vs 18.5%,P=0.550）比较,差异均无统计学意义。结论 TKI经治不可切除HCC患者可以从仑伐替尼治疗中获益...     

Impact of lenvatinib on renal function compared to sorafenib for unresectable hepatocellular carcinoma

Anti-VEGF drugs, such as tyrosine kinase inhibitors, play an important role in systemic therapy for unresectable hepatocellular carcinoma (uHCC). We examined the effects of sorafenib and lenvatinib on proteinuria and renal function.Patients who were administered sorafenib (n = 85) or lenvatinib (n = 52) as first line treatment for uHCC from July 2009 to October 2020, were enrolled in this retrospective observational study. A propensity score analysis including 13 baseline characteristics was performed. Eighty four patients were selected (sorafenib, n = 42; lenvatinib, n = 42) by propensity score matching (one-to-one nearest neighbor matching within a caliper of 0.2). We analyzed changes in estimated glomerular filtration rate (eGFR) during tyrosine kinase inhibitor treatment, as well as the development of proteinuria in both groups. A multivariate analysis was performed to identify predictors of a deterioration of eGFR.At 4, 8, 12, and 16 weeks, ΔeGFR was significantly lower in the lenvatinib group than in the sorafenib group (P < .05). The lenvatinib group showed a significantly higher frequency of proteinuria than the sorafenib group (30.9% vs 7.1%, P = .005) and had a higher rate of decrease in eGFR than the sorafenib group (P < .05). Multivariate analysis revealed that lenvatinib use was the only predictive factor of eGFR deterioration (odds ratio 2.547 [95% CI 1.028–6.315], P = .043). In cases of proteinuria ≤1+ during lenvatinib treatment, eGFR did not decrease. However, eGFR decreased in the long term (>24 weeks) in patients who have proteinuria ≥2+.Lenvatinib has a greater effect on proteinuria and renal function than sorafenib. In performing multi-molecular targeted agent sequential therapy for uHCC, proteinuria and renal function are important factors associated with drug selection after atezolizumab-bevacizumab combination therapy currently used as the first-line treatment.     

Long‐term antitumor effect of lenvatinib on unresectable hepatocellular carcinoma with portal vein invasion

Lenvatinib is a novel multikinase inhibitor that has recently shown antitumor activity against hepatocellular carcinoma (HCC) in a phase III trial. We report the case of a woman in whom lenvatinib showed long‐term antitumor activity, and in whom computed tomography (CT) scans revealed a series of suggestive radiological changes on the intratumor vascularity. A 68‐year‐old woman with hepatitis C virus‐related liver disease presented with multiple HCCs. Following previous therapy, including six sessions of transcatheter arterial chemoembolization, we introduced lenvatinib monotherapy. Lenvatinib could rapidly cause hypovascularity in the main hypervascular target lesion, and portal vein tumor thrombosis also became undetectable 11 months after the initiation of lenvatinib. These radiological changes suggested that lenvatinib could exert not only anti‐angiogenic activity but also direct antitumoral effect. Of note, CT scans during lenvatinib treatment revealed the target lesion as a low‐density area in the early arterial phase, whereas scans during drug interruption due to proteinuria showed that the lesion was enhanced in the arterial phase. Finally, near‐complete response could be achieved as the best response. We successfully managed various adverse events including proteinuria and hypertension, and the patient was able to continue this lenvatinib therapy for more than 4 years with well‐controlled general condition. We report the first case of a patient with HCC in whom lenvatinib monotherapy demonstrated long‐term antitumor activity. Suggestive radiological changes reflecting intratumor vascularity as presented here should be considered in patients receiving lenvatinib for HCC.     

Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study

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阶梯式管理对院外晚期肝细胞癌患者服用仑伐替尼的影响

目的　探讨院外晚期肝细胞癌（hepatocellular carcinoma, HCC）患者服用仑伐替尼治疗的新型护理管理模式,实现减少因仑伐替尼相关显性肝性脑病而中断或终止仑伐替尼治疗的病例。方法　采用单中心随机对照研究,评价以微信为媒介的闭合阶梯式护理管理院外晚期HCC患者服用仑伐替尼治疗的可接受性效果,以显性肝性脑病中断或终止仑伐替尼治疗为主要终点。结果　阶梯式护理管理组晚期HCC患者服用仑伐替尼12周内肝性脑病的诊断率为60.0%,明显高于家庭管理组的20.0%（P＜0.05）;经有效护理干预,阶梯式护理管理组持续服用仑伐替尼患者达93.3%,高于家庭管理组的80.0%;尤其因显性肝性脑病终止仑伐替尼治疗的病例患者仅为6.7%,低于家庭护理组的20.0%。结论　阶梯式护理管理院外晚期HCC患者服用仑伐替尼治疗可早期判定肝性脑病,是减少因仑伐替尼相关肝性脑病中断或终止治疗事件,延长晚期HCC患者生存期的必要手段。     

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

BACKGROUND Programmed death receptor-1(PD-1) inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC), but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE) and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of ...     

Radiotherapy for 65 patients with advanced unresectable hepatocellular carcinoma

AIM： To evaluate the efficacy of radiotherapy （RT） in patients with advanced unresectable hepatocellular carcinoma （HCC）. METHODS： A total of 65 patients were treated with RT in the Korea University Medical Center. The median age of the patients was 60 years, and 86.2% were men. 18.5% and 81.5% of the patients were diagnosed as TNM stage Ⅲ and Ⅳ-A, respectively. Treatment response was assessed 4 mo after initiation of RT. Tumor regression rate 1 mo after initiation of RT （TRR1m） was also assessed. Duration of survival was calculated from the initiation of RT. RESULTS： The objective treatment response was 56.9%. The 12 mo survival rate was 34.7%. Predictive factors for survival were Child-Pugh grade, α-fetoprotein level and treatment response. An objective response was achieved more frequently in patients with TRR1m ≥ 20% than in those with TRR1m 〈 20% （P 〈 0.001）. CONCLUSION： RT is effective in treating advanced HCC with a tumor response rate of 56.9%.     

Chemotherapy for transarterial chemoembolization in patients with unresectable hepatocellular carcinoma

AIM: To compare the efficacy of different chemotherapeutic agents during conventional transarterial chemoembolization (cTACE) in the treatment of unresectable hepatocellular carcinoma (HCC).METHODS: A retrospective review was undertaken of patients with unresectable HCC undergoing cTACE from May 2003 to November 2011. A total of 107 patients were treated with at least one cTACE session. Irinotecan (CPT-11) was used as a chemotherapeutic agent in 24 patients, gemcitabine (GEM) in 24 and doxorubicin in 59.RESULTS: The time to progression and overall survival rates were significantly superior in patients treated with CPT-11 compared with the GEM or doxorubicin treated groups (11.4, 8.2, 9.5 mo, P = 0.02 and 21.7, 12.7, 14.5 mo, P = 0.004, respectively). Subgroup analysis showed that for intermediate-stage HCC, CPT-11 resulted in a significantly longer time to progression and overall survival compared with the GEM or doxorubicin treated groups (P = 0.022; P = 0.003, respectively). There were no significant differences in adverse events among the three groups (P > 0.05).CONCLUSION: For patients treated with cTACE, the chemotherapeutic agent CPT-11 was significantly associated with improved overall survival and delayed tumor progression compared with GEM or doxorubicin. There were no significant differences in clinical adverse events between the three agents. CPT-11 thus appears to be a promising agent when combined with cTACE for the treatment of HCC.