Dataset Information

Physical activity improves outcomes of combined lenvatinib plus anti-PD-1 therapy in unresectable hepatocellular carcinoma: a retrospective study and mouse model.

ABSTRACT:

Background

Physical activity is known to have anti-cancer effects, including immunomodulatory actions. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC.

Methods

The physical activity levels of patients with unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy were recorded by questionnaire. Patients were categorized according to physical activity levels (active vs. sedentary). The primary outcome was overall survival (OS). Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). A subcutaneous syngeneic HCC model was generated in C57BL/6 mice. Mice were randomized to receive placebo, combined lenvatinib plus anti-PD-1 antibodies or combination therapy plus physical activity. Tumors were measured every 3 days and harvested for immunohistochemistry analysis at 20 mm maximum diameter.

Results

Fifty-nine patients with unresectable HCC were categorized to active (n = 28) or sedentary (n = 31) groups. The active group had higher albumin and des-γ-carboxy prothrombin levels and lower hepatitis B virus load at baseline; other clinical and oncologic characteristics were comparable between the two groups. Patients in the active group had significantly longer OS (HR = 0.220, 95% CI 0.060-0.799) and PFS (HR = 0.158, 95% CI 0.044-0.562) and higher ORR (OR = 4.571, 95% CI 1.482-14.102) than patients in the sedentary group. Regular physical activity was independently associated with OS, PFS and ORR. The mouse model showed that physical activity significantly suppressed tumor growth and prolonged survival of tumor-bearing mice. Furthermore, physical activity inhibited Treg cell infiltration and immune checkpoint expression (including CTLA4, TIGIT and TIM3) induced by long-term combined lenvatinib plus anti-PD-1 therapy, improving efficacy.

Conclusions

Regular physical activity was associated with improved outcomes in unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.

SUBMITTER: Liu XF

PROVIDER: S-EPMC8978397 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Physical activity improves outcomes of combined lenvatinib plus anti-PD-1 therapy in unresectable hepatocellular carcinoma: a retrospective study and mouse model.

Liu Xue-Feng XF Zhu Xiao-Dong XD Feng Long-Hai LH Li Xiao-Long XL Xu Bin B Li Kang-Shuai KS Xiao Nan N Lei Ming M Sun Hui-Chuan HC Tang Zhao-You ZY

Experimental hematology & oncology 20220404 1

<h4>Background</h4>Physical activity is known to have anti-cancer effects, including immunomodulatory actions. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC.<h4>Methods</h4>The physical activity levels of patients with unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy were recorded by questionnaire. Patients were categorized according to physical ac ...[more]

PMID: 35379324

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Project description:Background: Programmed cell death protein-1 inhibitors combined with lenvatinib have become a popular treatment option for patients with unresectable hepatocellular carcinoma. Transarterial chemoembolization combined with programmed cell death protein-1 inhibitors and lenvatinib has also shown preliminary efficacy in the unresectable hepatocellular carcinoma. We conducted this observational, retrospective, cohort study to compare the clinical outcomes and safety of transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib versus programmed cell death protein-1 inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma. Methods: Between November 2019 and November 2021, patients who were diagnosed with unresectable hepatocellular carcinoma and received transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib or programmed cell death protein-1 inhibitors plus lenvatinib treatment were reviewed for eligibility. The primary endpoints included objective response rate, overall survival, and progression-free survival. The secondary endpoint was the frequency of key adverse events. Results: In total, 105 patients were eligible for the present study, and they were divided into the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group (n = 46) and the programmed cell death protein-1 inhibitors plus lenvatinib group (n = 59). The patient cohort after a one-to-one propensity score matching (n = 86) was also analyzed. The transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had a higher objective response rate both in the patient cohort before propensity score matching (54.3% vs 25.4%, P = .002) and after propensity score matching (55.8% vs 30.2%, P = .017). The patients in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had prolonged overall survival (median, 20.5 vs 12.6 months, P = .015) and progression-free survival (median, 10.2 vs 7.4 months, P = .035). For patient cohort- propensity score matching, the overall survival (20.5 vs 12.8 months, P = .013) and progression-free survival (12.1 vs 7.8 months, P = .030) were also significantly better in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group than in the programmed cell death protein-1 inhibitors plus lenvatinib group. There were no significant differences between the 2 groups concerning adverse reactions caused by immunotherapy and lenvatinib. The adverse reactions caused by transarterial chemoembolization were transient and were quickly reversed. Conclusions: Compared to programmed cell death protein-1 inhibitors plus lenvatinib, transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib may provide better treatment response and survival benefits for patients with unresectable hepatocellular carcinoma, and the adverse events were manageable.

Project description:BackgroundLenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has proven efficacy as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, there is no standard effective second-line treatment option following progression on lenvatinib therapy. Because of the comprehensive coverage of therapeutic targets of lenvatinib, the remission rate of other TKI treatments in HCC patients resistant to lenvatinib is quite low.MethodsIn this study, the effectiveness and safety of anti-programmed cell death protein-1 (PD-1) antibodies plus lenvatinib were assessed in 46 patients between April 2018 and April 2020 at the Zhongshan Hospital, Fudan University, by retrospectively reviewing their clinical data. Patients with unresectable HCC who progressed on lenvatinib were given standard doses of lenvatinib and anti-PD-1 antibodies. They were followed-up every 6-8 weeks with medical imaging and laboratory tests and treatment-related adverse reactions were investigated.ResultsThe objective response and the disease control rates were 23.9% (11/46) and 71.7% (33/46), respectively by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST). After a median follow-up period of 15.6 [interquartile range (IQR), 11.2-22.0] months, the median progression-free survival (PFS) and overall survival (OS) were 6.9 months [95% confidence interval (CI): 2.1-11.8] and 14.5 months (95% CI: 6.8-22.3), respectively. The most common treatment-related adverse events were anorexia (43.5%), hypothyroidism (43.5%), hypertension (36.9%), fatigue (34.8%), and diarrhea (26.1%). Grade 3/4 events occurred in 16 patients (34.8%). Emotional functioning and overall quality of life were improved significantly following the initiation of anti-PD-1 antibodies plus lenvatinib therapy (fatigue, 4.9±7.5 vs. 11.1±12.7, P=0.03; diarrhea, 12.3±20.9 vs. 18.5±16.8, P=0.01; pain, 5.5±10.3 vs. 11.1±13.9, P=0.01).ConclusionsThe combination of anti-PD-1 antibodies and lenvatinib may benefit patients with unresectable HCC who progressed on lenvatinib. This study provides a real-world data and treatment choice for patients progressed with lenvatinib.

Project description:PurposeTo evaluate the efficacy and safety of lenvatinib combined with programmed death receptor-1 signaling inhibitors plus transarterial chemoembolization (LePD1-TACE) for treatment of unresectable hepatocellular carcinoma (uHCC) in a real-world setting in China.MethodsThis was a retrospective study involving consecutive patients with uHCC (n =114) receiving LePD1-TACE treatment from June 2019 to May 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were calculated to evaluate the antitumor efficacy. Treatment-related adverse events (TRAEs) were analyzed to assess the safety profiles. In addition, we also evaluated prognostic factors related to survival and disease progression.ResultsA total of 114 patients with a median age of 53 years were analyzed during a median follow-up duration of 10.6 months (95% confidence interval [CI]: 8.5 -12.8). The Kaplan-Meier analysis showed that the median OS was 18.0 months (95% CI: 14.1 - Not reached), the median PFS was 10.4 months (95% CI: 6.6 - 12.4). Based on modified Response Evaluation Criteria in Solid Tumors, the best ORR was 69.3% and DCR was 80.7%. Almost all patients suffered from TRAEs, the most common grade 3-4 TRAEs were hypertension (8.8%), proteinuria (3.6%), hyperbilirubinemia (1.8%), leukopenia (4.4%) and alanine aminotransferase elevation (3.6%) across all patients. The independent treatment factors associated with OS and PFS were tumor number, neutrophil-to-lymphocyte ratio (NLR) and the early tumor response. In the early tumor response (CR+PR) patients, median OS and PFS were 25.1 months (95% CI: 13.8 - Not reached) and 15.2 months (95% CI: 10.5 - 19.1). The patients with tumor number < 3 had a superior median OS and PFS (25.1, 16.4 months) compared to patients with tumor number ≥ 3 (14.1 months, P = 0.012; 6.6 months, P = 0.007). The patients with NLR ≤ 2.165 had a longer median OS and PFS (Not reached, 15.2 months) than those with NLR > 2.165 (17.7 months, P = 0.003; 7.5 months, P = 0.047).ConclusionIn this real-world study, LePD1-TACE triple therapy showed encouraging efficiency and manageable safety in patients with uHCC. The tumor number (< 3), NLR (≤ 2.165) and early tumor response (CR+PR) could be one of the prognostic markers.

Project description:BackgroundCombining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC).AimsTo explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC.MethodsThis multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety.ResultsBy March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events.ConclusionFirst-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.

Dataset Information

Physical activity improves outcomes of combined lenvatinib plus anti-PD-1 therapy in unresectable hepatocellular carcinoma: a retrospective study and mouse model.

Background

Methods

Results

Conclusions

Publications

Physical activity improves outcomes of combined lenvatinib plus anti-PD-1 therapy in unresectable hepatocellular carcinoma: a retrospective study and mouse model.

Similar Datasets

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