bluuebunny/crossref_metadata_2025_split huggingface dataset:
A retrospective study of the efficacy and safety of donafenib combined with TACE as adjuvant therapy in patients with high-risk recurrence factors after hepatocellular carcinoma surgery.
Authors: Zou Qifei , Yuan Shengxian 
Published: June 2023

e16121 Background: Surgical resection is the most important treatment for patients with hepatocellular carcinoma (HCC) to obtain long-term survival. However, the 5-year recurrence rate after hepatectomy is as high as 40%-60% and above. Reducing the postoperative recurrence rate is the key to improve the overall efficacy of HCC. This study aimed to evaluate the efficacy and safety of donafenib combined with TACE as adjuvant therapy in HCC patients with high-risk recurrence factors after surgical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high-risk recurrence factors who underwent surgical resection at Shanghai Eastern Hepatobiliary Surgery Hospital from April 2021 to October 2022. High-risk recurrence factors included: the number of tumors ≥ 3, tumor diameter ≥ 5 cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. Patients received adjuvant therapy of donafenib combined with TACE after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 40 patients were enrolled with a median age of 55.5 years (21-78), 39 patients (97.5%) in BCLC stage B and 1 patient (2.5%) in BCLC stage C. 33 patients (82.5%) were co-infected with HBV. All 40 patients had ECOG PS scores of 0 and Child-Pugh scores of A. A total of 34 patients (85%) with MVI were pathologically reported after surgery, 23 patients (57.5%) with tumor diameter ≥5cm, 9 patients (22.5%) with portal vein cancer thrombus, and 6 patients (15%) with satellite lesions. All patients received at least one TACE treatment after surgery, 31 patients (77.5%) received the TACE treatment one month after surgery, and 9 patients (22.5%) received the TACE treatment within one month after surgery. The initial dose of donafenib was 200mg/day. As of the cut-off date of data collection, the median follow-up time was 9 months (95%CI: 7.73-10.27), 4 patients relapsed and 2 patients died. The median RFS was 18 months (95% CI: 13.673-22.327), the one-year RFSR was 83.3% (95% CI: 61.9%-93.8%), and the one-year OS rate was 95.8% (95% CI: 75.2%-99.6%). 21 patients (52.5%) had combined treatment-related adverse events (TRAE), of which 4 patients (10%) had Grade 3 TRAE and no grade 4 or 5 TRAE were reported. Common adverse events included hand-foot skin reaction (9 patients, 22.5%), diarrhea (9 patients, 22.5%), rash (5 patients, 12.5%), hypertension, and gastrointestinal reactions (2 patients each, 5%). Conclusions: Donafenib combined with TACE was used for adjuvant therapy in patients with high-risk recurrence of HCC, which has a high one-year recurrence-free survival rate and was well tolerated.
Sequential therapy versus first-line tyrosine kinase inhibitor plus immune checkpoint inhibitor therapy for unresectable hepatocellular carcinoma.
Authors: Ruan Minghao , Yang Cheng , Zhao Jing , Zhi Kangkang , Feng Xiaochen , Zhang Jin , Jin Riming , Li Yao , Wu Dong , Liu Hui , Sun Wen , Wang Ruoyu 
Published: June 2023

e16122 Background: The treatment landscape of hepatocellular carcinoma (HCC) evolves, but the optimal sequential strategy for tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI)-based combination therapy is still unclear. This study compared the outcome and efficacy of TKI-(TKI+ICI) sequential therapy versus first-line TKI+ICI combination therapy in unresectable HCC. Methods: The patients who had received TKI (lenvatinib or sorafenib) plus ICI (anti-PD-1/PD-L1 monoclonal antibody) as first-line therapy or TKI-(TKI+ICI) sequential therapy were retrospectively included. Treatment efficacy (progression-free survival (PFS) and overall survival (OS)) to sequential therapy or TKI+ICI combination therapy as well as treatment-related adverse events (TRAEs) were assessed. Results: Among 392 patients included, 55 underwent TKI-(TKI+ICI) sequential therapy and 337 underwent first-line TKI+ICI combination therapy. The median PFS was significantly longer in TKI-(TKI+ICI) group than that in TKI+ICI group (16.2 months versus 7.7 months, HR 0.65 [0.47-0.90]; p=0.009). The median OS was not reached in TKI-(TKI+ICI) group and was 22.8 months in TKI+ICI group (HR 0.53 [0.33-0.83]; p=0.006). Multivariate analyses revealed that Child- Pugh score, BCLC stage and sequential therapy were independently associated with PFS. Child-pugh score, macrovascular invasion (MVI), AFP levels and sequential therapy were independently associated with OS. Subgroup analysis indicated that patients with younger age, male gender, an ECOG PS 1, Child-Pugh score A, HBV(+), HCV(-), BCLC stage C, presence of MVI or extrahepatic metastasis could remarkably benefit from sequential therapy. The survival outcome and objective response to TKI+ICI combination therapy was comparable between groups. The incidence of TRAEs were slightly higher in TKI-(TKI+ICI) group ( p=0.022), but the difference was not significant for Grade≥3 events ( p=0.126). Conclusions: TKI-(TKI+ICI) sequential therapy is a valid therapeutic strategy for patients with HCC compared with first-line TKI+ICI combination therapy.
Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.
Authors: Cheng Zhuo , Yang Cheng , Zhao Qian , Zhong Jingjiao , Zhang Jin , Jin Riming , Li Yao , Ta Na , Wu Dong , Yuan Zhengang , Sun Wen , Wang Ruoyu 
Published: June 2023

e16124 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) has shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. This study aims to assess the efficacy of ICIs in GBC and explore the clinicopathological and molecular markers of ICI benefit. Methods: This was a single center, retrospective study, including 80 GBC patients who had received ICI (anti-PD-1 monoclonal antibody) therapy at Eastern Hepatobiliary Surgery Hospital (Shanghai, China) between January 2016 and December 2020. Tumor samples from 31 of these patients who had previously underwent surgical resection before ICI therapy were obtained and conducted for whole exome sequencing and immunohistochemical analysis. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR) and disease control rate (DCR). The associations between efficacy with clinicopathological factors, genetic variations and PD-L1/CD8 expression were further explored. Results: Of 80 patients with GBC, 36 were male, the median age was 61 years (range, 30-79). The median PFS and OS was 4.5 months (95% CI, 2.99-5.95) and 8.7 months (95% CI, 7.07-10.26) respectively. Multivariate analysis indicated that alcohol intake history (HR, 2.66; 95% CI, 1.31-5.40; p=0.007), extrahepatic metastasis (HR, 2.03; 95% CI, 1.15-3.59; p=0.015), carcinoma embryonic antigen (CEA) level ≥100U/mL (HR, 3.58; 95% CI, 1.65-7.74; p=0.001) and immune-related adverse events (irAEs) (HR, 0.24; 95% CI, 0.10-0.57; p=0.001) were independent prognostic factors for PFS. Extrahepatic metastasis (HR, 2.42; 95% CI, 1.37-4.31; p=0.003), CEA level ≥100U/mL (HR, 2.82; 95% CI, 1.33-5.95; p=0.007) and irAEs (HR, 0.32; 95% CI, 0.14-0.72; p=0.006) were independent prognostic factors for OS. ORR and DCR were 13.75% and 37.5%, respectively. Patients with irAEs (85.7%, OR, 16.00; 95% CI, 3.26-78.61; p<0.001), high CD8+ T-cells-infiltrated GBCs (87.5%, OR, 19.83; 95% CI, 2.00-196.38; p=0.011), immune inflamed phenotype (66.7%, OR, 5.60; 95% CI, 1.16-27.08; p=0.032) had higher DCR, while patients with high level of total bilirubin (TBIL>34.2μmol/L) (8.3%, OR, 0.12; 95% CI, 0.01-0.97; p=0.048) had lower DCR. Patients with high CD8+ T-cells-infiltrated or immune inflamed GBCs also had a notably improved PFS and OS. Conclusions: ICIs were effective in patients with GBC. Alcohol intake history, extrahepatic metastasis, CEA level ≥100U/mL, irAEs, high positivity of CD8+ T-cells and immune inflamed phenotype may be useful for predicting the efficacy of ICIs in GBC.
Camrelizumab combined with lenvatinib and RALOX-HAIC for hepatocellular carcinoma (HCC) in BCLC stage B and C: A prospective, single-arm, phase II trial (Cal Era study).
Authors: Chen Jinzhang , Zang Mengya , Pang Huajin , Li Chuanjiang , Zhao Jianbo , Guo Yabing , Hou Jinlin 
Published: June 2023

e16128 Background: The combination of systemic therapies and hepatic arterial infusion chemotherapy (HAIC) showed promising outcomes for advanced hepatocellular carcinoma (HCC). Raltitrexed, an antimetabolic drug with long plasma concentrations half-life, could be used in short infusions. HAIC with raltitrexed plus oxaliplatin (RALOX) was reported to be effective and safe in HCC. This study aimed to investigate the efficacy and safety of combined camrelizumab and lenvatinib plus RALOX-HAIC as a first-line treatment in advanced HCC patients. Methods: This single-arm, phase II study included treatment-naive adult (≥18 years) patients with HCC in BCLC stage B and C and Child-Pugh score small or equal to 7 points (NCT05003700). Patients were administrated with RALOX-HAIC (oxaliplatin 100mg/m2, raltitrexed 3 mg/m2, every 3 weeks), combined with camrelizumab (200mg by IV infusion, every 3 weeks) and lenvatinib (8mg orally once daily) for 6 cycles, followed by maintenance therapy with camrelizumab and lenvatinib until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Results: Between March 2021 and October 2022, 36 patients (33 men and 3 women; median age, 54.5 years) were enrolled. The median tumor size was 11.4 cm, 86.1% of patients had portal vein invasion, and 38.9% had extrahepatic metastasis. As of February 1, 2023, the median follow-up was 14.2 months, and all patients had at least one post-baseline tumor assessment. The confirmed ORR per RECIST v1.1 and per mRECIST was respectively 61.1% (95% CI, 44.4−77.8), and 83.3% (95% CI, 70.5−96.1) including 4(11.1%) patients who achieved a complete radiological response. The median progression-free survival (PFS) time was 13.8 months (95%CI, 8.8-20.5) per RECIST v1.1. The 6-month and 12-month overall survival rate were 94.3% and 64.9%, respectively. Grade 3-4 treatment-related adverse events (AEs) occurred in 75% of patients, and the most common were neutropenia (44.4%) thrombocytopenia (36.1%), elevated aspartate aminotransferase (25.0%), and leucopenia (19.4%). All AEs were expected and manageable, and no treatment-related deaths were reported. Conclusions: Combination treatment with camrelizumab and lenvatinib plus RALOX-HAIC showed promising antitumor activity and acceptable toxicity in patients with advanced HCC. Clinical trial information: NCT05003700 .
Immunotherapy versus tyrosine kinase inhibitors in advanced hepatocellular carcinoma in first-line setting: A systematic review and meta-analysis of randomized controlled trials.
Authors: Marin Comini Ana Carolina Carolina , Sousa Isadora Martins de , Reis Pedro Cotta Abrahão , Carvalho Bruno Murad , Camandaroba Marcos Pedro Guedes 
Published: June 2023

e16132 Background: Hepatocellular carcinoma has a high mortality rate, with an overall 5-year survival of less than 20%. Whether the use of immune checkpoint inhibitors (ICI) is superior to tyrosine kinase inhibitors (TKI) as a first-line therapy remains unclear. Methods: We performed a systematic review and meta-analyses of randomized clinical trials (RCTs) to compare ICI, in monotherapy or combined with TKI or anti-VEGF monoclonal antibody in naïve treatment. We searched Embase, PubMed and Cochrane Library databases from inception to November 2022. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Overall Response Rate (ORR) and Treatment Related Adverse Events (TRAE). Using a random-effects model, statistical analysis was performed with RevMan 5.4 version for proportions and risk ratios for binary outcomes from comparative studies. Results: We included 10 RCTs comprising 6097 patients in the final analysis, 2554 in ICI monotherapy, 1096 in ICI with anti-VEGF and 2447 in ICI with TKI. The use of ICI, alone or in combination therapy, was associated with a better OS (HR 0.77; 95% CI 0.69–0.85; p< 0.00001; I²=46%) and PFS (HR 0.77; 95% CI 0.64-0.92, p=0.005; I²= 85%). In the ICI monotherapy subgroup, there was a statistical difference to TKI in OS (HR 0.82; 95% CI 0.75-0.91; p=0.0001; I² = 0%). Although there was a higher ORR in all ICI groups (RR 2.56; 95% CI 1.89-3.46; p<0.00001, I²=68%), TRAE Grades 3-4 (RR 0.85; 95% CI 0.61-1.18; p=0.33; I²=96%) presented no difference when compared with TKI. Conclusions: Our findings suggest that the use of ICI, alone or in combination with TKI or anti-VEGF, is a superior option for first-line therapy for advanced hepatocellular carcinoma, improving OS, PFS, and ORR without increasing treatment toxicity. These results are important for guiding clinical decision-making and further research in this field.
Gaps in care planning and delivery for patients with liver cancer: Baseline assessment for implementation of 4R Oncology model.
Authors: Therapondos George , Trosman Julia R. , Du Lingling , Mizrahi Jonathan , Sandow Tyler Allan , Cohen Ari , Gimenez Juan , Palmer Carol , Medina Amanda , O'Brien Michelle , Tan Amie , Weldon Christine B. 
Published: June 2023

e16136 Background: Liver cancer is a complex disease, requiring detailed care planning, patient engagement and delivery of comprehensive care, including supportive and health maintenance care. The 4R Oncology Model for patient facing care planning, patient self-management and team based delivery of complex care has the potential to address these needs. 4R (Right Info/Care/Patient/Time) significantly improves patient self-management and optimizes delivery of supportive and health maintenance care in breast and lung cancer (Trosman JCOOP 2021; Liu JCOOP 2022). The impact of 4R in liver cancer has not been examined. Ochsner Health’s multi-disciplinary live cancer team is implementing and evaluating 4R. Here we describe the baseline assessment of provider practices and patient experience of care planning and delivery of supportive and health maintenance care. Methods: Surveys of providers and patients on current care planning and delivery in liver cancer were conducted Oct 2022 – Jan 2023. We used 3 metrics of care planning and 3 metrics of care delivery (Table). Results: Survey response rates: providers 55% (33/60), patients 43% (27/63). Providers included physicians, advance practitioners, nurses and navigators from Hepatology, Transplant, Interventional Radiology and Medical Oncology. Patients were 56% female, 63% white, 37% black, 56% < 30k income. In care planning, patient experience was reported at a similar rate as provider practices for informed on goal of care, but significantly higher than providers for informed on next steps in care and receiving a detailed care plan (Table). In care delivery, patient experience and provider referral practices for social and supportive care were similarly low. Rates of patients’ receiving primary care and substance abuse assistance were significantly higher than respective rates of provider referrals. Among providers, 73% give patients a verbal care plan and 27% a hand written plan. The current process to create care plans is satisfactory to 54% of providers. Conclusions: We found substantial gaps in care planning and referrals to supportive and health maintenance care. Higher rates of patients reporting receipt of care planning and services suggest that many patients may resort to their own devices in these aspects of care. Ochsner Health aims to address these gaps by implementing the 4R Oncology model in liver cancer and will share results when available. [Table: see text]
Identification of prognostic tumor microenvironment in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy in combination with lenvatinib and PD-1 inhibitors.
Authors: Guo Wenbo , Chen Song , Zhao Lihua , Wu Zhiqiang , Cai Hongjie , Wang Fan , Wu Lijia 
Published: June 2023

e16141 Background: The triple combination therapy of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has shown promising outcomes in patients with advanced hepatocellular carcinoma (HCC) as a first-line treatment. However, the tumor microenvironment (TME) characteristics of the beneficiary population are still unclear. This study aimed to generally explore the TME characteristics of patients receiving the triple combination therapy by baseline tumor tissues. Methods: A total of 44 patients were prospectively enrolled in this single-center study. Ultimately, 38 biopsy-proven patients were treated with HAIC with oxaliplatin, leucovorin, 5-fluorouracil (FOLFOX), lenvatinib, and PD-1 inhibitors. According to the tumor response elevated by the modified RECIST (mRECIST), the 38 patients were divided into the response group with complete response (CR) and partial response (PR) and the non-response group with stable disease (SD) and progression disease (PD). Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were evaluated. Meanwhile, the cancer gene-targeted next-generation sequencing (NGS) and RNA sequencing (RNA-seq) were performed to describe the differences between the two groups of biopsy samples to identify the prognostic TME characteristics. Results: Among the 38 patients, 22 patients were distributed to the response group, and the remaining 16 patients were included in the non-response group. The response group and the non-response group were significantly different in median OS (not-reached vs. 8.6 months; HR, 0.22, 95% CI 0.08-0.58; p< 0.001) and median PFS (15.3 months vs. 2.0 months; HR, 0.31, 95% CI 0.13-0.75; p= 0.001). The most common AEs were AST elevation (84.2%), stomachache (76.3%), nausea (63.2%), and hypertension (52.6%). Grade 3/4 AEs occurred 14 times among 12 patients, and no treated-related deaths were observed. For the cancer gene-targeted NGS, no specific enrichment for gene mutations was identified to be related to prognosis. As for the TME analysis by RNA-seq, the response group was characterized by a more beneficial infiltration of immune cell subsets, and high tumor-infiltrating T lymphocytes were associated with a higher response rate, longer PFS and OS. Conclusions: In this study, HAIC plus lenvatinib and PD-1 inhibitor as first-line therapy displayed promising efficacy and manageable side effects in patients with advanced HCC. The differences in the initial TME of patients, especially in tumor-infiltrating T lymphocytes, may be potential biomarkers for predicting response and prognosis. This finding provides clues to search for biomarkers for the triple combination therapy of HAIC combined with lenvatinib and PD-1 inhibitors in advanced HCC.
Efficacy and safety of radiotherapy combined with regorafenib for advanced hepatocellular carcinoma: A real-world study from a single center.
Authors: Xin Lingxia , Wang Liming , Zhai Yirui , Wang Shulian , Tang Yuan , Liu Yueping , Song Yongwen , Fang Hui , Li Ning , Qi Shunan , Lu Ningning , Li Ye-Xiong , Chen Bo 
Published: June 2023

e16142 Background: This study aimed to assess the efficacy and safety of radiotherapy (RT) combined with regorafenib as a second or further-line treatment for advanced hepatocellular carcinoma (HCC). Methods: Patients diagnosed with advanced HCC who had received RT combined with concurrent or sequential regorafenib treatment or regorafenib plus anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors (ICIs) in our hospital from April 2018 to August 2022 were reviewed. Progression-free survival (PFS) was the primary endpoint. Overall survival (OS), objective response rate (ORR), disease control rate (DCR) and toxicity were the secondary endpoints. Results: Fifty-four patients were included with a median age of 56 (38-73). Forty-six patients (85.2%) were in Barcelona Clinic Liver Cancer (BCLC) stage C. Thirty-seven patients (68.5%) had portal vein tumor thrombosis and 15 (27.8%) had extrahepatic metastasis. All patients received intensity modulated radiation therapy, while 26 patients were concurrently treated with regorafenib and 28 patients were sequentially treated with regorafenib. The median dose of radiotherapy was 57.2Gy (30-69.8Gy). Anti-PD-1/anti-PD-L1 agents were applied to 31 patients at the use of regorafenib. The median PFS was 11.3 months. The 3-year PFS and OS were 23.8% and 51.9%, respectively. Treatment response after RT was shown. For tumor in in-field of RT, ORR was 75.9% and 92.6% according to RECIST and mRECIST criteria, respectively. No progression was found in in-field of RT. Out-field recurrence in liver and distance metastasis was the main failure pattern. For all lesions, the ORR was 40.7% and DCR was 55.6%, respectively. There was no significant difference of PFS and OS between patients with and without ICIs ( p > 0.05). Univariate analysis showed that alpha-fetoprotein tumor marker level ≥ 1000 ng/ml ( p = 0.049), Albumin-Bilirubin grade ≥ 2 ( p = 0.012) and multiple intrahepatic tumors ( p = 0.031) were the risk factors of lower PFS. Patients were well tolerated to the treatments. The most common grade 3 toxicities were hand-foot syndrome (11.1%), fatigue (3.7%) and hypertension (1.9%). Classical or non-classical radiation-induced liver disease was not noted. Conclusions: Radiotherapy concurrently or sequentially with regorafinib treatment is an effective, well tolerated, and promising regimen in advanced HCC patients. [Table: see text]