bluuebunny/crossref_metadata_2025 huggingface dataset:
A single-center, prospective, single-arm, phase II trial to evaluate the adjuvant efficacy of camrelizumab with docetaxel plus S-1 for stage III (PD-L1+/dMMR/EBV+) gastric cancer after D2 resection.
Authors: Ni Bo , Xia Xiang , Guan Yujing , Yang Linxi , Ji Linhua , Zhao Enhao , Cao Hui , Zhao Gang , Zhu Chunchao , Zhang Zizhen
Published: June 2023

e16089

Background: Immunotherapy has demonstrated promising efficacy and favorable safety profile for unresectable or metastatic gastric cancer (GC) by several high-quality studies. However, few have examined the immunotherapy efficacy for locally advanced GC (LAGC) in the perioperative setting, especially as adjuvant therapy after D2 resection. Here, a phase II trial reports the adjuvant efficacy of camrelizumab with docetaxel plus S-1 in patients (pts) with PD-L1 positive, deficient mismatch repair (dMMR) or Epstein-Barr virus (EBV) positive LAGC (NCT04152889). Methods: This is a single-center, prospective, open-label and single-arm phase II study. Chemotherapy-naive adult pts receiving D2 resection and histologically confirmed as PD-L1 positive (CPS > 5), dMMR or EBV positive LAGC (stage III) were enrolled. Pts received camrelizumab (200mg, D1), docetaxel (40mg/m2, D1, free at first course) and S-1 (80-120mg, D1-14) every 3 weeks for seven courses, sequenced by camrelizumab (200mg, D1) and S-1 (80-120mg, D1-14) every 3 weeks for up to one year, until disease relapse or intolerable toxicity. Primary endpoint was 1-year relapse-free survival (RFS). Herein, the safety and efficacy data after 1-year postoperative therapy courses were reported. Results: From Jan. 2020 to Jan. 2022, 19 pts (median age 59 years, range 34-75, 13 men and 6 women) were enrolled, of whom 15 were CPS > 5, 3 were dMMR, and 1 was EBV positive. pTNM stage IIIA, B and C were 10 (52.6%), 3 (15.8%) and 6 (31.6%), respectively. The cut-off date for the final follow-up data was Feb. 1, 2023 with a median follow-up period for surviving patients of 25.1 months. All 19 pts had experienced treatment related adverse events (TRAEs), of whom, grade 3-4 TRAEs occurred in 9 (47.4%), 2 pts (10.5%) discontinued therapy, and 11 pts (57.9%) delayed the therapy. Furthermore, the OS rate of 19 pts at 1/2 years was 100% and 88.9%, while the RFS rate at 1/2 years was 100% and 92.3%, respectively. The dead and recurrent cases all belonged to PD-L1 positive subgroup. Conclusions: Adjuvant therapy of camrelizumab with docetaxel plus S-1 shows acceptable safety and promising efficacy for PD-L1 positive, dMMR, or EBV positive stage III GC pts after D2 resection. Clinical trial information: NCT04152889 .
Variation of body composition and its impact on survival in a global population of patients receiving multimodal treatment for esophageal cancer.
Authors: Boshier Piers R , Low Donald E. ,   INSPECT Authors' Group
Published: June 2023

e16093

Background: Growing evidence has supported a role for body composition in predicting survival in patients undergoing esophagectomy. This study seeks to define baseline variation and clinical correlates of body composition in an international cohort of patients undergoing esophagectomy for cancer. Methods: Patients who underwent esophagectomy in fourteen high-volume centers between January 2007 to December 2019 were eligible for inclusion. Skeletal muscle, visceral and subcutaneous adipose tissues within CT images, acquired at the time of diagnosis, were analyzed by a single trained assessor in accordance with a standardized protocol. Survival status was censored June 2022. Results: In total 1716 patients were recruited to this study from three global regions: North America (n = 386; 22.5%), Europe (n = 940; 54.8%) and Asia (n = 390; 22.7%). Patients were predominantly male (79.5%) and adenocarcinoma was the most common histological subtype (66.6%). Wide variation in skeletal muscle (17.1 to 83.5cm2), visceral (0.2 to 170.1cm2) and subcutaneous adipose tissue (0.2 to 216.8cm2) was observed. Characteristics that were significantly associated with levels of muscle and adiposity were global region, sex, age and histological subtype. Compared to adenocarcinoma, SCC was associated with significantly (p < .0001) lower levels of muscle and adiposity, a finding that was independent of global region, sex, and age using a multivariable linear regression model (p < .0001). Reduced skeletal muscle and an excess of total adiposity at the time of diagnosis was associated with 90-day mortality and worse long-term survival. A nomogram including skeletal muscle, total adiposity at diagnosis and other tumor and patient specific variables was constructed to allow convenient survival prediction. Conclusions: This is the first study to assess parameters of body composition in a global cohort of patients receiving multimodal therapy for esophageal cancer. Findings highlight important regional and disease specific variation in body composition parameters and demonstrate the clinical utility of these measurements in predicting both early and late survival after esophagectomy. Results are intended to inform future guidelines for the use of body composition assessment in routine clinical practice.
Eligibility of patients with esophageal and gastroesophageal cancer for biology-guided radiotherapy in a retrospective cohort.
Authors: Olaechea Santiago , Song Tidie , Gilmore Linda , Infante Rodney E , Desai Neil B , Dan Tu , Zhang Yuanyuan , Westover Kenneth D. , Timmerman Robert D. , Oz Orhan K. , Iyengar Puneeth , Garant Aurelie
Published: June 2023

e16100

Background: Biology-guided radiotherapy (BgRT) is a novel radiotherapy modality that uses real-time positron emission tomography (PET) to guide radiotherapy beamlets. The FDA recently cleared BgRT for clinical use for tumors in lung and bone using 18F FDG radiotracer. We sought to identify esophageal cancer (EC) and gastroesophageal junction cancer (GEJC) patients who may be BgRT candidates based on diagnostic FDG PET/CT imaging. Methods: Through IRB-approved extraction of patient medical record data from an institutional repository of prospectively maintained data, we verified a database of EC and GEJC patients diagnosed at a US tertiary care center between 01/01/2006 and 12/31/2013. When insufficient diagnostic clinical information was present, patients were excluded. Patient and tumor qualities were quantified and subjected to parameters of tumor diameter (≥2cm, <5cm) and maximum standardized uptake value (≥6) to observe potential characteristics of a patient population eligible for this novel BgRT mechanism. Results: Thirty patients met tumor size and FDG uptake criteria for BgRT therapy out of an overall patient cohort of 90 patients. A significantly greater proportion of patients within the BgRT-eligible cohort presented with esophageal tumors (83.3%) compared to non-eligible patients (58.3%, P=0.0177). Otherwise, there was no significant variation of patient sex, race, tumor histology, tumor stage, comorbidity score, and pre-treatment weight loss between patients eligible and not eligible for BgRT therapy. Conclusions: After applying current boundaries of tumor size and radiotracer uptake for effective BgRT intervention, we observed broad applicability of the novel treatment modality across EC/ GEJC patients of varying characteristics and tumor qualities. The high eligibility of patients with tumors located within the esophagus supports further investigation of BgRT in their management. [Table: see text]
Clinical efficacy and safety of immune checkpoint inhibitor in combination with regorafenib therapy as second⁃line regimen for patients with unresectable hepatocellular carcinoma.
Authors: Li Jinpeng , Jia Yuntao , Song Jinlong
Published: June 2023

e16105

Background: Combined systemic and local therapy is a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKI) and PD-1 antibodies are all recommended for patients with unresectable HCC (uHCC). This study was aimed to evaluate the efficacy and safety of TACE combined with TKIs and camrelizumab in the treatment of uHCC. Methods: In this multicenter, single-arm phase II trial (ChiCTR2000039508), patients with intermediate-stage uHCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a TKI agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg), sorafenib 400 mg bid or donafenib 200 mg bid until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) per modified RECIST. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR) and overall survival (OS). Results: From September 2020 to November 2021, 87 patients (81 men and 6 women; median age, 56 years) were enrolled. Among them, 43 (49.4%) patients had extrahepatic metastases, and 65 (74.7%) patients had HBV infection. As of September 28, 2022, the median duration of follow-up was 13.6 (0.83-24.9) months. A total of 34 patients (39.1%) died, and the median OS was not reached. The median PFS was 10.5 months (95% CI: 7.8-13.1). The ORR rate was 71.3% (62/87), and the DCR rate was 89.7% (78/87) per mRECIST. According to RECIST version 1.1, the ORR rate was 35.6% (31/87), and the DCR rate was 87.4% (76/87). The ORR and PFS showed consistent benefits in subgroups based on ECOG score, HBV infection, baseline alpha-fetoprotein level, combined TKI, and the number of TACE treatments. Ten patients (11.5%) successfully underwent conversion therapy and all achieved R0 resection. Two patients achieved a complete pathological response (pCR) and four achieved a major pathological response (MPR). The most common AEs were hypoproteinemia (92%), elevated lactate dehydrogenase (80.5%), elevated glutamic oxaloacetic transaminase (79.3%), elevated bilirubin (78.2%), abdominal pain (62.1%), nausea (33.3%), and RCCEP (26.4%). The incidence of grade 3-4 adverse reactions was 67.8%, and no treatment-related deaths occurred. Conclusions: TACE combined with TKI and camrelizumab showed promising clinical benefits. It can effectively control tumor progression and provide opportunities for resection with acceptable safety, which will bring great benefits to uHCC.
Diagnostic and prognostic biomarker value of blood circulating inflammatory cytokines in hepatocellular carcinoma.
Authors: Chamseddine Shadi , Kaseb Ahmed Omar
Published: June 2023

e16115

Background: Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data has suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs has yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients. Methods: We prospectively collected data, and serum samples from 767 HCC patients treated at The University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% CI: 52.5, 83.3). Biomarker association with overall survival (OS) was evaluated by the Log-rank method. Results: The median OS in this cohort was 14.2 months (95% confidence interval [CI]: 12, 16.1 months). Clinicopathologic features were more advanced, and OS was significantly inferior in patients with high circulating levels of IL1-R1, IL-6, IL-8, IL-10, IL-15, IL-16, and IL-18. Conclusions: In conclusion, our study shows that several serum IL levels are valid prognostic biomarker candidates and potential targets for therapy in HCC.
Immune checkpoint inhibitor plus tyrosine kinase inhibitor with or without transarterial chemoembolization for unresectable hepatocellular carcinoma.
Authors: Pan Hongyu , Ruan Minghao , Jin Riming , Zhang Jin , Li Yao , Wu Dong , Sun Wen , Wang Ruoyu
Published: June 2023

e16123

Background: Transcatheter arterial chemoembolization (TACE) has been combined with immune checkpoint inhibitor (ICI)-based systematic therapies for unresectable HCC (uHCC) with promising efficacy. However, whether the addition of TACE to the combination of ICI and tyrosine kinase inhibitor (TKI) (ICI+TKI+TACE) is superior to ICI+TKI combination therapy is still not clear. Thus, this study compares the efficacy of ICI+TKI+TACE triple therapy and ICI+TKI doublet therapy in patients with uHCC. Methods: uHCC patients treated with either ICI+TKI+TACE triple therapy or ICI+TKI doublet therapy were retrospectively recruited between January 2016 and December 2021 at Eastern Hepatobiliary Surgery Hospital. The patients from ICI+TKI+TACE group and ICI+TKI group were further subjected to propensity score matching based on the baseline characteristics. The primary outcome was progression-free survival (PFS) in matched patients. The secondary outcomes were overall survival (OS) and objective response rate (ORR). Post-progression survival (PPS) as well as treatment-related adverse events (TRAEs) were also assessed. Results: A total of 120 patients were matched. The median PFS was 8.4 months in ICI+TKI+TACE triple therapy group versus 6.6 months in ICI+TKI doublet therapy group (HR 0.72, 95%CI 0.48-1.08; p=0.115). Similar results were obtained in term of OS (26.9 versus 24.2 months, HR 0.88, 95% CI 0.51-1.52; p=0.670). The ORR in the triple therapy group was comparable with that in the doublet therapy group (16.6% versus 21.6%, p=0.487). Further subgroup analysis for PFS illustrated that patients without previous locoregional treatment (preLRT) (10.5 versus 3.7 months, HR 0.35 [0.16-0.76]; p=0.009), without previous treatment (10.5 versus 3.5 months, HR 0.34 [0.14-0.81]; p=0.015) or treated with lenvatinib (14.8 versus 6.9 months, HR 0.52 [0.31-0.87]; p=0.013) can significantly benefit from triple therapy compared with doublet therapy. A remarkable interaction between treatment and preLRT ( p=0.049) or TKIs-combined ( p=0.005) was also detected in term of PFS. Kaplan-Meier analysis of PPS revealed that patients with post progression treatment displayed significant improved survival in both ICI+TKI+TACE and ICI+TKI groups. The incidence of TRAEs was comparable between two groups. Conclusions: In selected uHCC patients (without preLRT or treated with lenvatinib as combination), the addition of TACE to ICI+TKI combination therapy can remarkably improve PFS.
Arterial chemotherapy in advanced hepatocellular carcinoma: An evolutionary trajectory exploration and pooled outcome analysis.
Authors: Chen Qi-Feng , Lyu Ning , Zhao Ming
Published: June 2023

e16125

Background: Hepatic artery infusion chemotherapy (HAIC) is widely used for the treatment of advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, there have been inconsistent conclusions on the effectiveness of HAIC in previous studies, and the analysis landscape regarding relevant articles and clinical trials is lacking on this topic. We conducted a bibliometric analysis to explore the development of HAIC, and a pooled analysis using individual patient data to evaluate the outcomes of HAIC in advanced HCC. Methods: The Web of Science Core Collection was searched from its earliest records until October 2022, to identify studies associated with HAIC for advanced HCC. Relevant documents were collected and analyzed using R bibliometrix. During the same period, two international clinical trial registered platforms, ClinicalTrials.gov and ChiCTR.org, were searched for oxaliplatin-based HAIC utilization in HCC. A total of 845 patients treated with HAIC or its combination therapy from 17 pre-registered studies were analyzed to assess the overall survival (OS), progression-free survival (PFS), objective response rate (ORR per Response Evaluation Criteria in Solid Tumors (RECIST)), disease control rate (DCR per RECIST), and adverse events (AEs). Results: We identified 539 studies and derived the evolutionary trajectory of HAIC from the perspective of scientometry. Contributions of publications were presented at the country, institution, and author levels. Conversion therapy, Folfox, oxaliplatin and immunotherapy became new research foci. A total of 88 registered trials were identified and a comprehensive landscape of these trials was provided. Further interactive exploration of the trials was accessible through a HAICshiny application (https://sysucc.shinyapps.io/clinical-trial-of-HAIC-FO/). The OS was 13.7 months (95% confidence interval (CI) 12.2-15.3), and the corresponding times were 13.2, 13.8, 12.8, and 13.7 months in the cisplatin, oxaliplatin, HAIC monotherapy, and concomitant therapy subgroups, respectively. The corresponding PFS was 7.0 months (95% CI 6.5-7.8) in the whole cohort and 5.2, 7.7, 7.6, and 6.8 months in the subgroup cohorts. According to RECIST criteria, ORR and DCR reached 0.34 and 0.80, respectively. Comparable survival and tumor response were observed between the HAIC and its combination therapy groups. The incidence of AEs was identified, and most of them were manageable. Conclusions: This study illustrates the evolutionary trajectory of HAIC from the perspective of scientometry. The efficacy outcomes of HAIC in the treatment of advanced HCC were verified with manageable safety profiles. Further trials regarding HAIC implementation are emerging, and more effort is required to improve the quality of trials.
Regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma efficacy and safety of patients: A real-world study.
Authors: Bai Yi , Yu Jianfa , Cheng Chuanliang , Chen Dapeng , Zhang Yamin
Published: June 2023

e16126

Background: Results from the RESORCE-III RCT demonstrated that sequential sorafenib-regorafenib treatment significantly improved overall survival compared with the placebo group. However, there are no retrospective studies of regorafenib as a first-line agent for treating patients with advanced hepatocellular carcinoma in a real-world setting. Therefore, we aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with immune checkpoint inhibitors (ICIs) in treating patients with advanced hepatocellular carcinoma in a real-world setting. Methods: We reviewed medical data from 48 patients with advanced hepatocellular carcinoma treated with regorafenib as a first-line agent alone or combined with ICIs between December 2018 and February 2022. These patients were treated with regorafenib for at least 28 consecutive days (21 days on and 7 days off the drug). The progression-free survival (PFS), overall survival (OS), objective response rate (ORR, RECIST 1.1 criteria) and disease control rate (DCR) were observed. Results: A total of 48 patients were enrolled in this study, 26(54.2%) receiving regorafenib as monotherapy and 22(45.8%) receiving the combination ICIs. The median age in the monotherapy group was 54 years (range 38-74), male/female (69.2%/30.8%), BCLC stage B/C (42.3%/57.7%), Child-Pugh A/B score (57.7%/42.3%); the median age in the combined ICIs group was 53 years (range 42-75), male/female (68.2%/ 31.8%), BCLC stage B/C (36.4%/63.6%), Child-Pugh A/B score (54.5%/45.5%). Median PFS (mPFS) was 7.7 months (95% CI:5.9-10.4) and median OS (mOS) was 16.7 months (95% CI:14.3-23.6) in 48 patients. In the regorafenib monotherapy group, mPFS was 5.9 months (95% CI:5.6-10.3) and mOS was 13.9 months (95% CI:13.5-22.5); in the combined ICIs group, mPFS was 7.8 months (95% CI:7.3-14.5) and mOS was 23.6 months (95% CI:16.6-NA). The ORR and DCR were 20.8% and 72.9% in the overall treatment group, 15.4% and 65.4% in the monotherapy group, and 27.3% and 81.8% in the combined ICIs treatment group, respectively. Among the adverse events, rates were 34.6% (9/26) and 36.4% (8/22) in the monotherapy and combined ICIs groups, respectively, with only one grade III/IV adverse event in the monotherapy group and no grade III/IV adverse event in the combined ICIs group. Conclusions: This retrospective, real-world, preliminary study demonstrates that regorafenib as a first-line agent alone or in combination with ICIs has a high safety profile and more prolonged survival in patients with advanced hepatocellular carcinoma, particularly in combination with ICIs.
The impact of previous local therapy (LT) on overall survival (OS) in patients with advanced hepatocellular carcinoma (aHCC) treated with atezolizumab/bevacizumab (A+B) as first line systemic therapy.
Authors: Fierro Maria Elena , Alkadimi Munaf , Boyle Lauren Diaz , Lucero Kana , Mader Michael , Franklin Kathleen , Nooruddin Zohra
Published: June 2023

e16129

Background: Treatment options for aHCC have drastically improved over the past few years with immunotherapy at the forefront. Ongoing studies aim to identify the benefit of immunotherapy in combination with local therapies, but there are no studies that analyze the impact of previous local therapy on OS in patients who later receive A+B for treatment of aHCC. This study aims to analyze the impact of previous local therapy on OS in patients with aHCC treated with first line A+B within the Veterans Health Administration (VHA). Methods: Patients with aHCC receiving first line systemic therapy with A+B at VHA between Dec 1, 2019 through Mar 1, 2022 were identified from the electronic medical record (EMR) using ICD-9 and ICD-10 codes. Abstractors reviewed the EMR and followed the patients from the date of diagnosis, date of local treatment and date of A+ B initiation until death or their last VHA visit with the study period ending on Jan 31, 2023. The Chi-Squared test was used to compare rates and the Mann-Whitney test was used to compare medians. Results: 332 patients with aHCC received A+B. 67% of patients received prior LT. Patients who received LT had better ECOG status, Child-Pugh classification, and BCLC staging at time of diagnosis. There was no difference in age at diagnosis, race/ethnicity, ALBI score at time of diagnosis or at time of starting A+B, or presence of extrahepatic spread at time of starting A+B. There was a statistically significant difference in time from HCC diagnosis to start of A+B, with patients who received LT having a longer interval time. There was a small but not statistically significant difference in median OS from the start of A+B, favoring people who received LT. Conclusions: Our unique retrospective study confirms that patients receiving LT have better OS from the time of diagnosis. Disease biology and LT response may be contributing to this survival benefit. However, the OS was similar from the time of initiation of A+B in patients receiving LT versus patients who did not receive any LT.[Table: see text]
Novel peptide binder to Glypican-3 for targeted radiopharmaceutical therapy of hepatocellular carcinoma.
Authors: Li Gary , Lin Fanching , Clift Renee , Ehara Takeru , Yanagida Hayato , Horton Steven , Salvador Katrina , Richardson Samantha , Guest Matt , Noncovich Alain , Bhat Abhijit , Han Guangzhou
Published: June 2023

e16131

Background: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan primarily involved in embryonic development, and is barely detectable in normal adult tissues. Significant upregulation of GPC3 protein in hepatocellular carcinomas (HCC) has been observed in multiple immunohistochemistry (IHC) studies with up to 75% positivity rate, and is associated with poor prognosis. GPC3 is not expressed in healthy or non-malignant liver tissue. Targeting GPC3 could fulfill an unmet medical need for HCC, a leading cause of cancer-related deaths worldwide for which efficacious therapies are lacking. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for GPC3-targeted radiopharmaceutical therapy (RPT) to treat HCC. Methods: RAYZ-8009 is comprised of a novel macrocyclic peptide binder to GPC3, a linker, and chelator DOTA that can be complexed with different radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR), as well as a radioligand binding assay in human HCC cell line HepG2. The cross-species binding was assessed by radioligand binding using recombinant mouse, cynomolgus monkey, and human GPC3 proteins. Target-mediated internalization in HepG2 cells was measured using Microbeta at various time points. In vivo biodistribution with 177Lu, and anti-tumor efficacy studies using 225Ac were performed in HepG2 tumor-bearing athymic nude mice. Results: RAYZ-8009 showed high binding affinity to human GPC3 with a KD of 0.7 nM as determined by SPR. Binding affinity was maintained across mouse, cynomolgus monkey and human GPC3. Potent cellular binding was confirmed in GPC3+ HepG2 cells, and was independent of choice of isotope. 177Lu-RAYZ-8009 showed fast and efficient internalization with 42% internalized by 20 minutes in HepG2 cells. In vivo biodistribution of 177Lu-RAYZ-8009 showed tumor uptake of 19.8, 16.6, 16.4, and 8.8 %ID/g at 2, 24, 48, and 96 hours, respectively. Renal uptake was 16.1, 4.7, 1.6, and 0.7 %ID/g at the same timepoints, with tumor/kidney ratios of 1.3, 3.7, 11.3, and 15.0, respectively. Minimal uptake was observed in other normal tissues. Tumor-specific uptake and retention were also observed when tumors were implanted orthotopically with no uptake in non-malignant liver tissue. Furthermore, significant tumor growth inhibition and survival benefit were achieved with 225Ac-RAYZ-8009 in GPC3+ HCC xenografts. Conclusions: Preclinical pharmacodynamic, pharmacokinetic, biodistribution and efficacy data demonstrate the potential of RAYZ-8009 as a RPT agent for the treatment of patients with GPC3-positive HCC.
TACE combined with the intra-arterial infusion of sintilimab and bevacizumab for advanced hepatocellular carcinoma: A prospective, single-arm, phase II study.
Authors: Mu Maoyuan , Fu Xiaobo , Qi Han , Jiang Weiwei , Chen Zixiong , Gao Fei
Published: June 2023

e16133

Background: Combination treatment with an immune checkpoint inhibitor and an anti-VEGF antibody is recommended as the standard care for advanced hepatocellular carcinoma (HCC). However, the efficacy of systemic therapy is less than satisfactory in BCLC stage C. Transarterial chemoembolization (TACE) combined with systemic therapy may synergistically improve patients’ clinical outcomes and obtain survival benefits. Intra-arterial infusion of Sintilimab and Bevacizumab has not been assessed previously. This study aimed to evaluate the safety and efficacy of TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab in patients with BCLC stage C HCC. Methods: This prospective, single-arm phase II study recruited 16 patients with advanced HCC. Main inclusion criteria: aged ≥ 18 years; a confirmed HCC (BCLC stage C) based on the ALSLD with either pathological or imaging findings; no previous systemic/locoregional anticancer treatment; Child-Pugh score ≤7; ECOG performance status: 0-1. Patients were treated with TACE (30-40mg of pirarubicin, 30-40mg of lobaplatin, and lipiodol) plus Sintilimab (200mg, intra-arterial infusion, d1, Q3W) and Bevacizumab (7.5mg/kg, intra-arterial infusion, d1, Q3W) for four cycles, followed by maintenance therapy with Sintilimab (200mg, intravenously, d1, Q3W) and Bevacizumab (15mg/kg, intravenously, d1, Q3W) to a maximum total cycle of eighteen unless any evidence of disease progression or unacceptable side effects. The primary endpoint was objective response rate (ORR) (assessed with mRECIST v1.1) and the secondary endpoints included disease control rate (DCR), time to progress (TTP), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: From September 2021 to December 2022, 16 patients with a median age of 52 years (range:38 -73) were enrolled. 12 (75%) patients with HBV infection and 6 (38%) with extrahepatic metastasis. 14 (88%) patients were classified as Child-Pugh A class. With a median follow-up of 5.4 months (range 3.9-14.3), the ORR was 63% (95%CI, 36.4%- 84.8%) with 3 CR and 7 PR per mRECIST v1.1, and the DCR was 69% (95%CI, 41.3%-89.0%). The median PFS was not reached. Adverse events in 31% of 16 patients were hypertension (3, 19%), fatigue (1, 6%), and proteinuria (1, 6%). The most common adverse event of grade 3 was hypertension (2, 13%). There were no treatment-related serious adverse events. Conclusions: TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab as the first-line strategy for advanced HCC patients (BCLC stage C) demonstrated a promising value by improving ORR, with acceptable side effects. Clinical trial information: NCT04796025 .
Anlotinib combined with transarterial chemoembolization for unresectable hepatocellular carcinoma associated with hepatitis B virus: A retrospective controlled study.
Authors: Guo Wenbo , Chen Song
Published: June 2023

e16138

Background: Hepatocellular carcinoma (HCC) has the third-highest cancer-related mortality rate in the world because most patients are diagnosed at an intermediate to advanced stage when surgery is not suitable. Transcatheter arterial chemoembolization (TACE) is currently considered a first-line therapy for unresectable HCC (uHCC), while the efficacy of TACE alone for uHCC patients still needs to be improved. Anlotinib has shown survival benefits in the treatment of uHCC as a kind of novel tyrosine kinase inhibitors (TKIs) in previous studies. Therefore, we aimed to compare clinical outcomes of TACE combined with anlotinib versus TACE monotherapy in patients with uHCC associated with hepatitis B virus (HBV). Methods: We retrospectively collected the data of 96 uHCC patients associated with hepatitis B virus who received either TACE only (TO group; n = 64) or anlotinib combined with TACE (TA group; n = 32) between January 2017 to January 2021. The clinical outcomes including overall survival (OS), progression-free survival (PFS), and tumor response according to mRECIST and RECIST 1.1 were compared between the two groups. Adverse events (AEs) were analyzed to assess the safety profiles. Results: The median OS in the TA group was 17.6 months (95%CI, 11.3 to 24.3) versus 9.4 months (95% CI, 7.8 to 16.3) in the TO group (hazard ratio, 0.59; 95% CI, 0.39 to 0.90; p= 0.018). The median PFS was also significant longer in the TA group (6.7 vs. 3.8months; hazard ratio, 0.46; p< 0.001). Additionally, the objective response rate (ORR) and disease control rate (DCR) numerically increased in the TA group (mRECIST: ORR 65.6% vs. 46.9%, p= 0.064; DCR 90.6% vs. 85.9%, p= 0.382. RECIST 1.1: ORR 46.9% vs. 15.6%, p= 0.001; DCR 90.6% vs. 85.9%, p= 0.382; respectively). No treatment-related mortality occurred. The most common AEs included elevated transaminases (56.3%), decreased appetite (46.9%) and abdominal pain (37.5%) in TA group. Though the incidence rate of grade 3/4 was higher in TA group, all of them were acceptable and controllable. Conclusions: Anlotinib combined with TACE may significantly improve outcomes for uHCC patients associated with hepatitis B virus comparing with TACE monotherapy with a controllable safety profile. Randomized controlled trials with a large sample are warranted to further validate the efficacy.
Efficacy and safety of transarterial chemoembolization in combination with lenvatinib and tislelizumab for patients with unresectable BCLC-B stage hepatocellular carcinoma classified as beyond up to seven criteria: A retrospective study.
Authors: Chen Song , Guo Wenbo
Published: June 2023

e16147

Background: Transarterial chemoembolization (TACE) is the preferred therapeutic regimen for patients with intermediated-stage (BCLC-B stage) unresectable hepatocellular carcinoma (uHCC). However, selected patients with high tumor burden have shown improved survival with systemic treatment, including targeted therapy, immunotherapy, or combination of them. This study was to evaluate the efficacy and safety of combination therapy for BCLC-B stage uHCC beyond up to seven criteria. Methods: In total, 120 patients enrolled in the study during 2015-2021, which were divided into 3 groups according to receive different treatment, and each group just comprised 40 patients. One group received treatment with TACE only (T group), and the other two groups received TACE combined with Lenvatinib (T+L group) and TACE combined with Lenvatinib and tislelizumab (T+L+P group) respectively. We retrospectively compared the clinical outcomes including overall survival (OS), progression-free survival (PFS) and tumor response among the three groups. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Besides, adverse events were collected to assess the safety as well. Results: The median duration of follow-up for all the patients was 28 months [95% CI, 22.8-34.2 months]. The median OS (mOS) was 24.2 months among patients in T+L+P group, as compared with15.0 months among patients receiving TACE alone (HR 0.32; 95%CI 0.19-0.55; P<0.001). The mOS was 20.6 months in T+L group (HR in comparison with TACE only, 0.54; 95%CI 0.34-0.85; P=0.008). The mOS was longer in T+L+P group comparing with T+L group (HR 0.49; 95%CI 0.29-0.85, P=0.011). The similar median PFS (mPFS) benefit was also detected among 3 groups (T+L+P vs. T HR 0.35; 95%CI 0.21-0.58; P<0.001. T+L vs. T HR 0.57; 95%CI 0.36-0.90; P=0.007. T+L+P vs. T+L HR 0.53; 95%CI 0.33-0.84; P=0.003). There was no significant statistic difference observed in objective response rate (ORR) and disease control rate (DCR) between each two groups ( P>0.05). Grade 3 or 4 adverse events (AEs) occurred more common in T+L group or T+L+P group, which was mainly due to target-related or immune-related AEs. There was no mortality happened related to treatment. Conclusions: TACE combined with lenvatinib and tislelizumab may significantly improve clinical outcomes both compared with TACE alone and TACE combined with lenvatinib with a manageable safety profile for BCLC-B stage uHCC beyond up to seven criteria. Nevertheless, it is necessary to be validated by means of prospective randomized control studies in future.
HER3 expression status following systemic chemotherapy treatment in biliary tract cancers.
Authors: Nishioka Mariko , Morizane Chigusa , Okada Mao , Satake Tomoyuki , Hiraoka Nobuyoshi , Nara Satoshi , Kakegawa Tomoya , Kobayashi Maki , Koyama Kumiko , Esaki Minoru , Okusaka Takuji
Published: June 2023

e16153

Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is frequently overexpressed in a variety of cancers. Activation of HER3 signaling serves an important role in promoting cell proliferation and is associated with chemoresistance. Thus, there is interest in exploring HER3 status of tumors as a potential prognostic and/or therapeutic target. Prior studies have reported HER3 status in various cancers after treatment with chemotherapy (CT). However, HER3 expression profile in biliary tract cancer (BTC) remains unknown. Here, we evaluated HER3 status of patients with BTC post CT. Methods: The medical records of patients (pts) who had been initially diagnosed with BTC and treated at the National Cancer Center Hospital (Tokyo, Japan), between January 2010 and June 2020, were retrospectively analyzed. Pts whose post CT specimens were available were included in this study. Immunohistochemical staining for HER3 was performed using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: A total of 19 pts with BTC, with a median age of 59 (range 44-79) years, had specimens available after post CT and were evaluated for HER3 expression status. HER3 status was 3+ in 10 pts, 2+ in 3 pts, 1+ in 4 pts, and 0 in 2 pts. The specimens were obtained from liver in 17 pts, bone in 1 pt, and omental lymph node in 1 pt. The histological type was adenocarcinoma in all pts, and HER3 status according to primary tumor type is shown in the table below. Fourteen pts were treated with gemcitabine (GEM) plus cisplatin (CDDP), 1 pt with GEM plus CDDP plus S-1, 1 pt with GEM plus S-1 as first-line CT for advanced BTC, and 3 pts with S-1 as an adjuvant treatment. Fifteen pts were biopsied after CT to participate in clinical trial. The remaining 4 obtained specimens after CT during primary surgery or surgery for metastases or for cholangitis. The median overall survival of pts with advanced BTC was 23.6 months in HER3 3+, 17.1 months in HER3 2+, 27.7 months in HER3 1+, and 24.6 months in HER3 0. Four pts had specimens available from pre and post CT, all of which were intrahepatic cholangiocarcinoma with the treatment of GEM plus CDDP. HER3 status was upregulated in 3 pts (1 pt 1+ to 2+, 2 pts 2+ to 3+) and downregulated in 1 pt (1+ to 0) at post CT. Conclusions: HER3 expression (1+, 2+, 3+) was observed in 89.5% of previously treated pts with BTC, and HER3 status was upregulated after CT in some pts. These results suggest that HER3 might be a potential therapeutic target in BTC post CT. [Table: see text]
Real-world experience and outcomes of immune-checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC).
Authors: Paul Samuel , Min Eric , Benson Katherine K , Xu Menglin , Noonan Anne M. , Mittra Arjun , Malalur Pannaga G. , Roychowdhury Sameek , Jin Ning , Hays John L. , Elkhatib Rifat T. , Rahman Shafia , Miller Eric David , Diaz Pardo Dayssy Alexandra , Manne Ashish
Published: June 2023

e16155

Background: Effective management of HCC needs concerted efforts of all the disciplines involved. ICI and its combinations have not improved the outcomes to the expected level outside clinical trials. This is a retrospective review of HCC patients treated with ICI in an academic institution. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 7/31/2021 at the Ohio State University were included in the study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, log-rank test rank test for survival outcomes, and logistic regression model for categorical outcomes using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort has 38 patients. The median age is 67 years (range 41-88), with 82% males and 90% Caucasians (7% African American and 3% other). Refer to the table for other BL characteristics. Median overall survival (OS) and progression-free survival were 6 months (m) (95% confidence interval [CI], 4-10) and 4m (95% CI, 3-6), respectively. The OS was better in patients with longer DoT (≤ 2m vs 3-6m vs ≥6m, 2m vs 5m vs 24m, p<0.001). Even though PFS was significantly better in patients with CP A-B9 (Vs B9-C, 6m vs 2.5m, p=0.03) and CP B (vs A vs C, 9m vs 5m vs 2m, p=0.02), OS was not different. Poor responders (<2 m vs ≥ 3m PFS) in this cohort had higher BL total bilirubin (TB) (p=0.03) and are more likely to have CPC (p=0.03) or CP B9-C (p=0.01) and BCLC D (p=0.04) patients. CP class (lower, p=0.0007), DoT (≥ 6m, p=0.0001), combination with bev (p=0.004), fewer liver lesions (≤2, < 0.001), no history of any LRT (p=0.01) or fewer LRTs (p=0.01), and non-metastatic disease (p< 0.001) are associated with better OS. PVTT, line of therapy, and ALBI G did not impact the OS. IrAE were reported just 4 (10%) patients. Conclusions: In this small retrospective cohort, lower volume of hepatic HCC lesions, use of ICI with bev, lower TB, longer DoT were associated with better OS, while more advanced disease, CPC, BCLC D, more LRTs and higher bilirubin resulted in worse survival. Our results suggest that prescribing ICI in line with FDA approval indications results in better outcomes. They must be validated in larger studies. [Table: see text]
Locoregional plus systemic therapy for unresectable intrahepatic cholangiocarcinoma: A systematic review and meta-analysis.
Authors: Qiu Zhenkang , Zhang Mengqi , Qiu Wensheng , Wang Song
Published: June 2023

e16157

Background: The outcome of systemic therapy (ST) for unresectable intrahepatic cholangiocarcinoma (iCCA) is poor. This study aims to further evaluate the efficacy and safety of locoregional plus systemic therapy (LST) compared with only ST in unresectable iCCA by performing a systematic literature review and meta-analysis. Methods: A comprehensive search comparing LSTs and STs for unresectable iCCA was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 3, 2022. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results: Ten cohort studies with 3,791 unresectable iCCA patients were enrolled in this study, including 1,120 who received ablation, arterially directed therapy (ADT), or radiotherapy (RT) combined with ST. The meta-analysis showed that the LST group had a longer OS ( HR = 0.51; 95% CI = 0.41–0.64; p value < 0.001) and PFS ( HR = 0.40, 95% CI = 0.22–0.71, p value = 0.002) and a better ORR ( RR = 1.68; 95% CI = 1.17–2.42; p value = 0.005). Subgroup analysis based on the type of locoregional treatment showed that both ST combined with ADT ( HR = 0.42, 95% CI = 0.31–0.56, p value < 0.001) and RT ( HR = 0.67, 95% CI = 0.63–0.72, p value < 0.001) could prolong OS. Combination with locoregional treatment does not result in additional severe AEs. Conclusions: Compared with only ST, LST improved survival outcomes for unresectable iCCA patients without increasing severe AEs, which can further provide a basis for guidelines.
Lenvatinib in combination with PD-1 inhibitor and hepatic arterial infusion chemotherapy (HAIC) for patients with potentially resectable hepatocellular carcinoma: A retrospective analysis.
Authors: Dong Wei , Zhang Songyan , Huo Zhuoni , Lu Junrong , Liu Haishi , Wang Ping , Zhang Yubao
Published: June 2023

e16160

Background: Surgical resection is the primary radical treatment for hepatocellular carcinoma (HCC). However, the percentage of initially resectable HCC is only 15-30%, and most patients are unable to undergo surgical resection at the time of initial diagnosis. Lenvatinib combined with PD-1 inhibitor and transarterial intervention has demonstrated good efficacy and safety in unresectable HCC. The retrospective study was designed to explore the safety and conversion effects of lenvatinib + camrelizumab+ HAIC in potentially resectable HCC. Methods: In this single-arm retrospective study, investigators collected patients with potentially resectable HCC treated with lenvatinib + camrelizumab + HAIC from November 2020 to December 2022. The potentially resectable population was selected by the following screening criteria: acceptable liver function (Child-Pugh A-B), good ECOG PS (0-1), intrahepatic tumors confined to one lobe (left, right, or middle lobe), and unresectable by surgical or oncological causes. Results: A total of 64 patients with potentially resectable HCC were included in this analysis. The conversion rate was 31.25% (20), and 23.4% (15) patients underwent surgery. The ORR and DCR were 56.3% and 85.9% by RECIST 1.1. Progression had occurred in 8 patients by the data cutoff on November 1, 2022. The median follow-up time was 13.6 months (range: 2.9-23.7) and 8 patients died. The data was not yet mature, with 1-year survival rate of 90.7%, Overall, 65.6% of patients experienced at least one treatment emergent adverse event (TEAE) and 15.6% of patients had Grade 3/4 TEAE, the most common was hand and foot syndrome (7.8%, n=5). Conclusions: Lenvatinib combined with PD-1 inhibitor and HAIC was well tolerated and showed potential conversion efficacy in the treatment of patients with potentially resectable HCC.
Regorafenib second-line therapy for surgical recurrent hepatocellular carcinoma: An exploration of continuing regorafenib therapy after tumor progression—A single-center retrospective analysis of 90 cases.
Authors: Wu Liqun , Rao Wei , Guan Ge , Xin Yang , Niu Qinghui , Fan Ning , Guo Yuan , Li Zixiang , Wang Song , Cai Jinzhen
Published: June 2023

e16164

Background: To explore the prognosis of patients with continuing regorafenib therapy after the HCC progression of second-line regorafenib therapy. Methods: The HCC patients with second treatment by regorafenib from Dec. 2017 to Dec. 2021 were collected from His system of the hospital. The inclusion criteria included surgical treatment with hepatectomy or liver transplantation, the HCC diagnosis by pathological confirmed, Child-Pugh A-B and ECOG PS≤2 when taking regorafenib, exposure time ≥21 days. Efficacy was evaluated according to RECIST v1.1 (solid tumor efficacy Evaluation Criteria). Results: By Dec. 31, 2022, the median follow-up time was 17.6 months since taking regorafenib. The median overall survival (OS) time was 26.0 months (95%CI 19.75-32.25 months) in 110 patients with second-line regorafenib treatment for recurrent HCC after surgical treatment, and the median OS time of first-line sequential regorafenib was 37.6 months (95%CI 30.23-44.97 months). In 100 cases of regorafenib progression, 10 cases received only palliative therapy after progression. The ninety cases continued the antitumor therapy, the median OS time after progression was 18.0 months (95%CI 12.93-23.07). There were 56 patients (62.2%) who continued to take regorafenib and 34 patients (37.8%) who took other targeted drugs. The median OS time after progression in the two groups was 18.0 and 19.8 months, respectively (P=0.614). In 56 patients who continued regorafenib, Kaplan-Meier analysis and Cox regression risk model analysis showed that NLR≥4.0, liver tumor load larger and without combination therapy were independent risk factors for survival after progression in patients with continued regorafenib. Conclusions: The overall survival time 18.0 months was found in patients with HCC progression after second-line regorafenib therapy, these patients with recurrent HCC underwent surgical treatment (resection or liver transplantation). There was no significant difference in OS time between those who continued regorafenib therapy and those who selected other targeted agents after HCC progression with the regorafenib. The NLR≥4.0, liver tumor load lager, and without combination therapy were independent risk factors for survival after progression in patients who continued regorafenib.
Gemcitabine, cisplatin, nab-paclitaxel: The effectiveness of this regimen for gall bladder cancer.
Authors: Chaugule Deepali , Bhargava Prabhat Ghanshyam , Ostwal Vikas S. , Srinivas Sujay , Patil Rajshree Nivrutti , Ghadi Aayushi , Vadodaria Divya , Munot Pritesh Naresh , Joarder Ritam , Vaidyanathan Arvind , Goel Mahesh , Patkar Shraddha , Ramaswamy Anant
Published: June 2023

e16168

Background: Locally Advanced inoperable/metastatic Gallbladder Cancers (GBC) are treated with either GC, GO, or single-agent Gemcitabine based on physician discretion. However, based on about 50% response rates (ORR) and prolonged survival in the phase II trial of biliary tract patients, were treated with Gemcitabine - Cisplatin - Nab-Paclitaxel (GCNP). Methods: Consecutive series of patients diagnosed with locally advanced (liver infiltration > 5 cm, large nodes at porta, abutting duodenum), inoperable and metastatic biliary tract patients between January 2018 to August 2022 were evaluated for first-line chemotherapy GCNP, in the Multidisciplinary Joint Clinic (MDJC). The primary endpoint was ORR and the secondary endpoints were survival and tolerance. Results: A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52 years (range: 21- 79), the majority were females (61.3%), and the majority were GB (81.7%). Response rates were available in 137 patients. CR, PR, and SD were seen in 9 (6.3%), 87 (61.3%), and 24 (16.9%) respectively, for a RR of 67.6% and CBR of 84.5%. Median EFS was 9.92 (95% CI, 7.69- 12.14) months. Of the 52 patients in whom GCNP was given with NACT intent for locally advanced GBC, 17 patients underwent surgery (34%). Conclusions: Our study indicates that GCNP leads to better response rates, better chances of unresectable disease being surgically feasible at a later date, and possibly offers better survival in the GBC cohort.