Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.     

Molecular targeted therapy for advanced hepatocellular carcinoma

Systemic anticancer therapy for hepatocellular carcinoma (HCC) is limited by intrinsic drug resistance and accompanying liver dysfunction. However, recent advances in molecular targeted therapy (MTT) have shed light on the treatment of advanced HCC. A recent randomized, placebo-controlled trial demonstrated that sorafenib, a multi-target tyrosine kinase inhibitor, prolonged overall survival and time-to-progression in patients with advanced HCC. This breakthrough highlights the potential of MTT targeting hepatocarcinogenic pathways, such as the Raf/MAPK/ERK pathway, angiogenic pathways and the EGFR signaling pathway. This review discusses the current status and the potential of developing novel MTTs for advanced HCC.     

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study

PurposeTo report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib.MethodsEligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed.ResultsThere were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab.ConclusionsWe report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits.Clinical trial registrationNCT01140347.     

Electrochemotherapy as treatment option for hepatocellular carcinoma,a prospective pilot study

Background and objectives

Electrochemotherapy provides non-thermal ablation of cutaneous as well as deep seated tumors. Based on positive results of the treatment of colorectal liver metastases, we conducted a prospective pilot study on hepatocellular carcinomas with the aim of testing the feasibility, safety and effectiveness of electrochemotherapy.

An open-label,single-arm,phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma

Purpose

We conducted this phase I/II clinical trial to determine the safety and efficacy of lower-dose decitabine based therapy in pretreated patients with advanced HCC.

Experimental Design

Patients with advanced HCC were eligible. The administered dose of decitabine was 6 mg/m²/d intravenously on days 1 to 5 of a 28-day cycle. Additional therapies were given based on their disease progression status. The endpoint was to ensure the safety, hepatotoxicity, clinical responses, progression-free survival (PFS) and pharmacodynamics assay of lower-dose decitabine.

Results

Fifteen patients were enrolled. The favorable adverse events and liver function profiles were observed. The most beneficial responses were 1 complete response (CR), 6 stable disease (SD) and 8 progressive disease (PD). MRI liver scans post-treatment indicated a unique and specific characteristic. The immunohistochemistry result from the liver biopsy exhibited noteworthy CTL responses. Median PFS was 4 months (95% CI 1.7, 7), comparing favorably with existing therapeutic options. Expression decrement of DNMT1 and global DNA hypomethylation were observed in PBMCs after lower-dose decitabine treatment.

Conclusion

The lower-dose decitabine based treatment resulted in beneficial clinical response and favorable toxicity profiles in patients with advanced HCC. The prospective evaluations of decitabine administration schemes and tumor tissue-based pharmacodynamics effect are warranted in future trials.     

Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma

Objective. Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC. Methods. In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment. Results. The 16W-DCR was 42% (95% confidence interval, 27%-57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3-4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04). Conclusion. Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.     

Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China

BackgroundRegorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear.MethodsThis was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4–6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS).ResultsA total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8–16.2] months, and the median OS was 17.0 (95% CI: 12.8–21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3–4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073–0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051–0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063–0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009–0.608; P=0.015) before 2nd-line treatment were independently associated with PFS.ConclusionsThe sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.     

Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial

BackgroundThe oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.MethodsIn this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4–10 and 18–24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.ResultsMedian overall treatment duration with any study drug was 9.9 months (range 0.6–19.6); median treatment duration with regorafenib was 7.7 months (range 0.1–19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5 months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.ConclusionRegorafenib + mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.ClinicalTrials.gov identifier: NCT01289821.     

A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma

Purpose: A multi-centre randomized phase II study of single agent nolatrexed dihydrochloride versus doxorubicin was undertaken in Chinese patients with advanced hepatocellular carcinoma (HCC) to study and compare the clinical efficacy of the two drugs. Methods: Fifty-four patients with clinical or histological diagnosis of HCC were randomized in a 2:1 ratio to receive nolatrexed or doxorubicin. Nolatrexed 725 mg/m²/day was given by continuous infusion via a central venous device for 5 days and doxorubicin 60 mg/m² was given as a rapid intravenous infusion every 3 weeks. Results: No objective responses were observed in either treatment arm. Two patients in the nolatrexed arm and none in the doxorubicin arm had >50% decline in serum α-fetoprotein. The median survival for the patients in the nolatrexed and doxorubicin arms was 139 days and 104 days, respectively. Moderate toxicities including leukopenia, thrombocytopenia, mucositis and skin rash were observed in both treatment arms. Conclusion: Nolatrexed and doxorubicin are minimally active in the treatment of advanced HCC. Given the small sample size, no difference is observed between the two drugs. Received: 26 October 1998 / Accepted: 20 January 1999     

免疫治疗联合分子靶向药物治疗中晚期肝细胞癌的临床疗效及安全性分析:一项单臂回顾性研究

目的 探讨免疫治疗联合分子靶向药物治疗中晚期肝细胞癌(HCC)的临床应用价值和安全性。方法 按照入组标准,纳入33例接受免疫治疗联合分子靶向药物治疗的中晚期HCC患者。记录患者用药前的血液生化指标、肿瘤分期、肿瘤影像学特征、既往接受的治疗策略等临床资料,随访患者的影像学复查结果及患者用药过程中发生的不良反应事件,直至随访截止、失访或患者死亡。主要研究终点为客观缓解率(ORR)及安全性,次要研究终点为无进展生存期(PFS)和总生存期(OS)。采用Kaplan-Meier法分析用药患者的临床疗效。结果 截至末次随访,共33例中晚期HCC患者接受了免疫药物与分子靶向药物的联合治疗,ORR为24.2%,疾病控制率(DCR)为66.7%。中位无进展生存期(mPFS)为10.9个月,中位总生存期(mOS)为11.8个月。治疗相关1~2级不良反应事件及发生率分别为恶心呕吐2例(6.1%)、手足皮肤反应2例(6.1%)、反应性皮肤毛细血管增生症2例(6.1%)、乏力1例(3.0%)、胃痛1例(3.0%)、蛋白尿1例(3.0%)、腹痛9例(27.3%)、发热1例(3.0%)、胀气1例(3.0%)、低蛋白血症1例(3.0%)、高胆红素血症5例(15.2%)、谷丙转氨酶升高4例(12.1%)以及谷草转氨酶升高10例(30.3%)。治疗相关3级以上不良反应事件及发生率分别为恶心呕吐1例(3.0%)、腹痛1例(3.0%)和谷草转氨酶升高1例(3.0%)。未观察到与治疗相关死亡事件,不良反应事件均得到有效处理。结论 免疫药物与分子靶向药物的联合使用在中晚期HCC的治疗中,DCR高,不良事件发生率低,可作为中晚期HCC患者一线治疗的选择,值得进一步探索。     

Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label,single-arm,phase II clinical trial

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.     

Innovative therapy for hepatocellular carcinoma: Three-dimensional high-dose photon radiotherapy

The development of three-dimensional conformal radiotherapy (3DCRT) has enabled high dose radiation to be directed to tumour with a frank sparing of the non-tumour surrounding liver parenchyma without restriction due to tumour topography and size, presence of peritumourous satellite nodules or associated segmental portal vein thrombosis. 3DCRT can be safely delivered alone or concomitantly with transarterial chemoembolization (TACE), giving very encouraging results. Efficacy is strongly related to a smaller tumor size and higher dose of radiation while toxicity closely correlates to the pre-radiotherapy liver functions and the dose delivered to the uninvolved liver. These data has led to integrate 3DCRT in the multimodal treatment of HCC as a possible curative-intent option as well as surgical resection or percutaneous procedures although phase-III controlled studies are warranted to clarify this point. This may represent a promising approach in patients who are inoperable or for whom other ablation therapies are not feasible. The next steps will be the optimization of delivery modes of this type of photon therapy, taking account that other radiation modalities such as proton beam therapy for instance might be shown as of great interest within the next few years.     

Recent update on comprehensive therapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The treatment methods for HCC are diverse, mainly including surgical resection, ablation, and liver transplantation. The curative effect can be achieved only for early stage HCC, and it is easy to recur and metastasize after surgery, with a 5-year recurrence rate as high as 70%. Most patients with HCC are in the middle and advanced stage at the time of diagnosis and lose the chance of surgical resection. In recent years, with the in-depth study of the pathogenesis of HCC and the progress of medical science and technology, the systemic treatment of advanced HCC has made a breakthrough. At present, multidisciplinary comprehensive treatment including targeted therapy and immunotherapy has become an effective strategy and inevitable trend for the treatment of advanced HCC. Combined therapy has greatly improved the prognosis of HCC patients and opened up a new milestone in the treatment of this malignancy. In this article, we focus on the treatment progress of advanced HCC to further guide clinical practice.     

Phase II study with a combination of epirubicin, cisplatin, UFT, and leucovorin in advanced hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC. Patients and methods: All 53 patients received epirubicin (50 mg/m² i.v.) on day 1 and cisplatin (60 mg/m² i.v.) after epirubicin administration. Oral UFT 400–600 mg/day, determined by body surface area, and leucovorin 75 mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval. Results: Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0–26.8%) with median response duration of 17.1 weeks (95% CI; 5.0–29.3 weeks, range; 7.1–51.7 weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6 weeks (95% CI; 17.3–31.9 weeks, range; 3.0–131.3 weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%). Conclusion: The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC. Contract grant sponsor: Brain Korea 21 Project in 2002 and Korea Health 21 R &D Project, Ministry of Health & Welfare, Republic of Korea: 01-PG3-PG6-01GN07-0004.