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Lenvatinib plus hepatic arterial infusion of modified FOLFOX regime in patients with advanced hepatocellular carcinoma.
Abstract
e16603
Background: Recently, Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of modified FOLFOX regime has shown promising results for patients with advanced hepatocellular carcinoma. Lenvatinib is also the first-line treatment for advanced hepatocellular carcinoma, it has shown the better objective response rate (ORR) and longer progression free survival (PFS) than sorafenib. This retrospective study evaluated the combination of lenvatinib plus HAIC of modified FOLFOX regime in patients with advanced hepatocellular carcinoma. Methods: This study retrospectively enrolled and analyzed 24 patients from Nov 2018 to May 2019 from Guangdong provincial people’s hospital. Patients with advanced hepatocellular carcinoma were treated with 8 mg(≤60kg) or 12mg( > 60kg) lenvatinib once daily plus HAIC of modified FOLFOX regime (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks). Best response according to the RECIST 1.1 and mRECIST criteria. PFS, overall survival (OS) and treatment-related adverse events(TRAE) were also evaluated. Results: 24 patients(median age: 49.2 years) underwent a total of 91 cycles of HAIC therapy (mean: 3.79; range: 2-8). 22 (91.7%) patients had cirrhosis caused by HBV infection.17(70.8%) patients were diagnosed with vascular invasion and 7 (29.2%) were both vascular invasion and extrahepatic spread. 20 (83.3%) patients were classified as Child-pugh A class and 4 (16.7%) patients were Child-pugh B class. The ORR were 58.3% (RECIST) and 66.7% (mRECIST), the disease control rate (DCR) was 79.2% (RECIST/mRECIST). With a median follow-up period of 11.3 months, the median PFS was 8.1 months. 6-, 9-, and 12-months OS rates were 91.7, 83.3%, and 75%, respectively. TRAE occurred in 20 of 24 patients (83.3%), most common TRAE were hypertension (41.7%) and hand-foot skin reaction(25%). No grade 3/4 TRAE was observed. Conclusions: Lenvatinib plus HAIC of modified FOLFOX regime was well tolerated and had shown promising ORR, PFS and 6-, 9-, and 12-months OS rates in advanced hepatocellular carcinoma. A prospective large-scale trial is needed to justify these results. [Table: see text]
... Data regarding the combination of HAIC with lenvatinib are limited. A retrospective study of 24 patients treated with HAIC plus standard-dose lenvatinib reported an encouraging ORR of 58% and a disease control rate of 79% [48]. Additional prospective studies of the combination of HAIC and lenvatinib are ongoing. ...
... Although no single regimen has been reported to demonstrate superiority over the others, differences may still exist among different regimens and various protocols. For example, doublet chemotherapy appeared to be associated with higher ORRs (30-40%) [26,44,46] compared with platinum alone (20-30%) [22,23,28,54]; moreover, regimens with higher doses (e.g., 5-FU at a total dose of >2000 mg/m2 or modified FOLFOX6) [23,42,[47][48][49] probably engendered higher ORRs than did those with low doses of 5-FU (40-70% vs. 30-40%) [22,28,38,54]. Investigators in China have reported encouraging results with consistent use of modified FOL-FOX6 as an HAIC regimen, particularly when used in combination with PD-1/PD-L1 blockade [47][48][49][50]. ...
... For example, doublet chemotherapy appeared to be associated with higher ORRs (30-40%) [26,44,46] compared with platinum alone (20-30%) [22,23,28,54]; moreover, regimens with higher doses (e.g., 5-FU at a total dose of >2000 mg/m2 or modified FOLFOX6) [23,42,[47][48][49] probably engendered higher ORRs than did those with low doses of 5-FU (40-70% vs. 30-40%) [22,28,38,54]. Investigators in China have reported encouraging results with consistent use of modified FOL-FOX6 as an HAIC regimen, particularly when used in combination with PD-1/PD-L1 blockade [47][48][49][50]. Notably, two Phase 3 trials, ATTRACTION-4 [65] and CheckMate-649 trials [66], which both compared oxaliplatin-based chemotherapy with or without PD-1 blockade in advanced gastric cancer, showed longer OS in the combination arm. ...
Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.
... In this regard, evidence suggests the clinical efficacy of arteriallydirected therapy can be improved through combination regimens such as lenvatinib with TACE or HAIC or lenvatinib with PD-1 inhibitors and HAIC, with ORRs reported to be 53.1-68.3%, 19,20 66.7%, 21 and 67.6%. 22 Hence, we conducted a study to investigate the effectiveness and safety of triple combination consisting of lenvatinib with sintilimab plus arterially-directed therapy as conversion therapy for patients with initially unresectable intermediatestage and advanced HCC patients, and explored the clinical outcomes. ...
Purpose
The purpose of this study was to investigate the triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC).
Patients and Methods
We retrospectively analyzed data from all HCC patients who underwent lenvatinib plus sintilimab plus arterially-directed therapy at Tianjin Medical University Cancer Hospital between December 2018 and October 2020. Of 98 enrolled patients, 37 patients were classified as potentially resectable. We compared the potentially resectable population (PRP) with the non-potentially resectable population (NPRP). The primary study endpoint was conversion rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.
Results
The baseline characteristics were comparable between populations except for a higher proportion of patients with extrahepatic metastases in the NPRP versus PRP (23/61 [37.7%] vs 3/37 [8.1%], respectively; p=0.003). For PRP, the ORR was 67.6% based on RECIST v1.1 (75.7% based on mRECIST), conversion rate was 40.5% (15/37). Of the 15 patients who underwent surgical resection, three achieved complete pathological remission. The median follow-up for all patients was 28 months (range: 2–47). For NPRP, the ORR was 22.9% based on RECIST v1.1 (31.1% based on mRECIST), The median PFS for PRP was significantly longer than that of NPRP (25 vs 13 months, p = 0.0025). The median OS for PRP was significantly longer than that of NPRP (not reached VS 21 months, p=0.014). Hypertension was the most common grade ≥3 adverse reaction in both PRP and NPRP. No new safety signals were observed for any of the treatments.
Conclusion
The triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy can convert potentially unresectable HCC into resectable disease and improve long-term survival.
... There are scarce data on the combination therapy of HAIC and lenvatinib. High ORR and DCR of 58.00% and 79.00% after combination therapy of HAIC and lenvatinib were observed in 24 advanced HCC patients in a retrospective study [28]. Consistent with this, our study demonstrated ORR and DCR of 66.70% in the combination therapy group, in which one patient achieved CR, confirming the superior efficacy of the combination therapy. ...
Background:
For patients with advanced hepatocellular carcinoma (HCC), hepatic artery infusion chemotherapy (HAIC) is a common and mature treatment, but the safety and efficacy of HAIC combined with lenvatinib for advanced HCC patient treatment remains unclear. Therefore, this study compared the safety and efficacy of HAIC with or without lenvatinib in unresectable HCC patients.
Methods:
We retrospectively analyzed 13 unresectable advanced HCC patients who received HAIC monotherapy or combination therapy of HAIC and lenvatinib. Overall survival (OS), disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), incidence of adverse events (AEs) and changes in liver function were compared between the two groups. We applied a Cox regression analysis to evaluate the independent risk factors affecting survival outcomes.
Results:
The ORR in the HAIC+lenvatinib group was markedly increased compared to the HAIC group (P<0.05), while the DCR in the HAIC group was higher (P>0.05). No notable difference was found between the two groups in median OS and PFS (P>0.05). Compared to the HAIC+lenvatinib group, more patients had improved liver function in the HAIC group after treatment, but the difference was not dramatical (P>0.05). The AEs incidence was 100.00% in both groups, which was relieved with corresponding treatment. Besides, Cox regression analysis did not identify independent risk factors related to OS and PFS.
Conclusion:
Combination therapy of HAIC and lenvatinib notably performed better than the HAIC monotherapy in patients with unresectable HCC in terms of ORR and was well tolerated, which deserves further investigation with large-scale clinical trials.
... TKIs+local therapy (22)(23)(24)(25) Compared with monotherapy, TKIs combined with local therapy had better conversion effectiveness and improved OS and PFS in patients with HCC and portal vein invasion. ...
Radical hepatectomy is the main treatment method to improve the prognosis of patients with intermediate and early-stage liver cancer. Most liver cancer patients in China are in the advanced stage at the initial diagnosis, losing the opportunity for surgical treatment. Therefore, it is essential to down-stage unresectable liver cancer to resectable liver cancer clinically, which is an important way to improve patients’ survival and a hotspot of current clinical research. In recent years, with the increase in effective treatment methods for liver cancer, the resection rate of conversion surgery for unresectable advanced liver cancer has been significantly improved, and a growing number of patients benefit from conversion therapy. This article mainly reviews the connotation of conversion therapy for liver cancer, the patient selection, the selection of conversion strategy, the timing of sequential operations, the scheme and safety, etc.
... ,37 A conference abstract showed that lenvatinib plus HAIC of modified FOLFOX regime had shown promising ORR (58.3%) and PFS (8.1 months).38 ...
Background:
Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma, but prognosis is still unsatisfactory. Recently, hepatic arterial infusion chemotherapy (HAIC), and immune checkpoint inhibitors showed promising results for advanced hepatocellular carcinoma. Considering different anti-malignancy mechanisms, combining these three treatments may improve outcomes. This study aimed to compare the efficacy and safety of lenvatinib, toripalimab, plus HAIC versus lenvatinib for advanced hepatocellular carcinoma.
Methods:
This was a retrospective study including patients treated with lenvatinib [8 mg (⩽60 kg) or 12 mg (>60 kg) once daily] or lenvatinib, toripalimab plus HAIC [LeToHAIC group, lenvatinib 0-1 week prior to initial HAIC, 240 mg toripalimab 0-1 day prior to every HAIC cycle, and HAIC with FOLFOX regimen (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 h, every 3 weeks)]. Progression-free survival, overall survival, objective response rate, and treatment-related adverse events were compared.
Results:
From February 2019 to August 2019, 157 patients were included in this study: 71 in the LeToHAIC group and 86 in the lenvatinib group. The LeToHAIC group showed longer progression-free survival (11.1 versus 5.1 months, p < 0.001), longer overall survival (not reached versus 11 months, p < 0.001), and a higher objective response rate (RECIST: 59.2% versus 9.3%, p < 0.001; modified RECIST: 67.6% versus 16.3%, p < 0.001) than the lenvatinib group. In addition, 14.1% and 21.1% of patients in the LeToHAIC group achieved complete response of all lesions and complete response of the intrahepatic target lesions per modified RECIST criteria, respectively. Grade 3/4 treatment-related adverse events that were more frequent in the LeToHAIC group than in the lenvatinib group included neutropenia (8.5% versus 1.2%), thrombocytopenia (5.6% versus 0), and nausea (5.6% versus 0).
Conclusions:
Lenvatinib, toripalimab, plus HAIC had acceptable toxic effects and might improve survival compared with lenvatinib alone in advanced hepatocellular carcinoma.
Hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX-HAIC) has shown a strong anti-tumor effect in hepatocellular carcinoma in China. Different from hepatocellular carcinoma in China, hepatocellular carcinoma in Western countries is caused by hepatitis C and alcoholic liver disease, and is often diagnosed at an early stage, when the tumor is small or the thrombus is not serious. Although there are no reports of FOLFOX-HAIC efficacy for hepatocellular carcinoma in Western countries, FOLFOX-HAIC can be used in patients with large tumors (> 5 cm) (or T3 by TNM stage), and rich blood supply.
Hepatocellular carcinoma is one of the deadliest neoplasms around the world, and a major proportion of patients are diagnosed in an advanced state not amenable to curative treatment. Lenvatinib, a promising first-line targeted therapy, has shown antitumour activity in both preclinical studies and clinical trials. Emerging evidence indicates that a combination of lenvatinib plus anti-PD-1 inhibitors or locoregional therapies exerts a stronger antitumour effect than monotherapy and even offers the possibility of long-term survival while maintaining acceptable tolerability. Several studies have also shown the superiority of lenvatinib over sorafenib in combination strategies. This review addresses the rationale behind lenvatinib-based combination therapies and comprehensively summarizes various clinical studies investigating lenvatinib in combination with immune checkpoint inhibitors (ICIs), locoregional therapies, and other systemic treatments. We discuss the unsatisfactory search for suitable biomarkers and key ongoing trials in this field.
Background:
Recently, hepatic arterial infusion chemotherapy (HAIC) plus lenvatinib has been frequently used to treat unresectable hepatocellular carcinoma (uHCC) in China. In the clinic, the hepatic arteries of some patients shrink significantly during this treatment, leading to improved short-term efficacy.
Aim:
To investigate the relationship between the shrinkage of hepatic arteries and the short-term effect of HAIC plus lenvatinib treatment.
Methods:
Sixty-seven participants with uHCC were enrolled in this retrospective study. The patients received HAIC every 3 wk, followed by oral lenvatinib after the first HAIC course. Hepatic artery diameters were measured on CT before treatment and after 1 and 2 mo of treatment. Meanwhile, the changes in tumor capillaries were also examined on pathological specimens before and after 1 mo of treatment. The antitumor response after 1, 3, and 6 mo of treatment was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The relationship between the changes in vessel diameters and the short-term effect of the combination treatment was evaluated by receiver-operating characteristic and logistic regression analyses.
Results:
The hepatic artery diameters were all significantly decreased after 1 and 2 mo of treatment (P < 0.001), but there was no difference in the vessel diameters between 1 and 2 mo (P > 0.05). The microvessel density in the tumor lesions decreased significantly after 1 mo of combination treatment (P < 0.001). According to mRECIST, 46, 41, and 24 patients had complete or partial responses after 1, 3, and 6 mo of treatment, respectively, whereas 21, 21, and 32 patients had a stable or progressive disease at these times, respectively. Shrinkage of the tumor-feeding artery was significantly associated with the tumor response after 1, 3, and 6 mo of treatment (P < 0.001, P = 0.004, and P = 0.023, respectively); however, changes in other hepatic arteries were not significantly associated with the tumor response. Furthermore, shrinkage of the tumor-feeding artery was an independent factor for treatment efficacy (P = 0.001, P = 0.001, and P = 0.002 and 1, 3, and 6 mo, respectively).
Conclusion:
The hepatic arteries shrank rapidly after treatment with HAIC plus lenvatinib, and shrinkage of the tumor-feeding artery diameter was closely related to improved short-term efficacy.
Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.
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