bluuebunny/crossref_metadata_2025 huggingface dataset:
Anlotinib hydrochloride combined with tislelizumab, paclitaxel liposome, and nedaplatin regimen for preoperative neoadjuvant therapy of esophageal cancer: A single-arm, single-center, phase II exploratory clinical study.
Authors: Ma Jie , Liu Cuizhen , Laoguo Shi-xue , Zhou Huafu , Wang Yongyong , Guo Jianji , Yang Lihua , Tang Jing , Li Rong , Zeng Zhiming , Dai Lei , Mo Ning , Zeng Jie
Published: June 2023

e16082

Background: Local recurrence and distant metastasis are important causes of high mortality in patients with locally advanced esophageal cancer. Neoadjuvant therapy combined with surgery can significantly improve the prognosis of patients with locally advanced esophageal cancer. Based on the clinical data of anlotinib (a multi-targeted tyrosine kinase inhibitors) and tislelizumab (anti-pd-1 antibodies), paclitaxel liposome (a cytotoxic anti-tumor drugs) and nedaplatin (a platinum-based anti-tumor drugs) in patients with esophageal cancer, to evaluate the efficacy and safety of anlotinib hydrochloride combined with tislelizumab, paclitaxel liposome and nedaplatin in preoperative neoadjuvant therapy for patients with stage IIB-IVA esophageal cancer. Methods: This study included 18-75 years old, ECOG PS 0-1 patients with potentially resectable stage IIB-IVA esophageal cancer with a predicted survival time of ≥12 weeks and confirmed by histopathology or cytology. Patients who met the inclusion criteria received anlotinib (oral, 12mg/d1-14,Q3W) combined with tislelizumab (intravenous drip, 200mg/d1,Q3W), paclitaxel liposome (intravenous drip, 175mg/m2/d1,Q3W) and nedaplatin (intravenous drip, 80mg/m2/d1,Q3W). After 2 cycles of neoadjuvant therapy, surgery was performed, and 4-6 weeks of chemotherapy combined with targeted immune adjuvant therapy was performed after the operation, and then Anlotinib combined with tislelizumab targeted immune maintenance therapy was performed until the disease progressed. Subjects who failed to complete at least one cycle of clinical trials according to this program due to non-experimental drug factors, and seriously violated this research program, such as: failure to follow the prescribed dose, method and course of medication, will be excluded from this study. The primary endpoint was objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), R0 resection rate, and pathological complete response rate. Results: From October 2021 to February 2023, 38 patients were included in this study, and clinical data of 27 patients can be used to track and evaluate clinical efficacy. The median age of the subjects was 58.5 years (range 47-75 years). the primary study end point was an ORR of 77.8% (95% CI，61%-94.5%). Conclusions: We will strictly implement the research protocol and objectively evaluate the anti-tumor activity and safety of anlotinib hydrochloride combined with tislelizumab, paclitaxel liposome and nedaplatin regimen in the treatment of patients with stage IIB ~ IVA esophageal cancer. In order to provide a safe and reliable neoadjuvant therapy for patients with locally advanced esophageal cancer. Clinical trial information: ChiCTR2100049693 .
Effect of multi-omics analysis on tumor ecosystem during neoadjuvant dose-limiting chemotherapy combination with sequential PD-1 blockade for patients with esophageal cancer.
Authors: Song Qi , Yang Bo , Xiong Qi , Wang Zhanbo , Long Yaping , Dong Zhouhuan , Zhou Wenhao
Published: June 2023

e16085

Background: Patients with esophageal cancer benefited from neoadjuvant chemotherapy combined with immunotherapy. However, the sequence of administration during neoadjuvant therapy remains under considerable debate. Methods: A study on 23 enrolled patients with esophageal cancer who received 2 cycles of neoadjuvant treatment of dose-limiting chemotherapy combined with sequential pembrolizumab and 2 cycles of adjuvant treatment of dose-limiting chemotherapy combined with sequential pembrolizumab was carried out. Serial plasma samples were collected and subjected to T cell receptor (TCR) sequencing. Tissues with pre- and post-neoadjuvant therapy were obtained and performed with whole-exome sequencing and transcriptome sequencing. Results: After neoadjuvant therapy, the percentage of patients with a pathological major response (MPR) was 39.1% (9/23), consisting of 21.7% (5/23) completed pathological response (cPR). TCR sequencing analysis showed that the peripheral blood-dominated TCR clones significantly augmented during the neoadjuvant treatment. Tumor mutational burden (TMB) was higher in the MPR group than in the non-MPR group at baseline. In addition, infiltrating CD8+ T cells increased and regulatory T (Treg) cells decreased in the MPR group after neoadjuvant therapy. While Treg cells increased in the non-MPR group after neoadjuvant treatment. Conclusions: Dominated TCR clones increased during the neoadjuvant limited-dose chemotherapy stage, which would contribute to sequential PD-1 blockade. Additionally, TMB, CD8+ T cells, and Treg cells are associated with clinical benefits during treatment.
The effect of inflammatory-nutri̇tional prognosti̇c scori̇ng (INPS) system on treatment response and prognosi̇s i̇n pati̇ents wi̇th locally advanced gastroesophageal juncti̇on and gastri̇c cancer wi̇th neoadjuvant systemi̇c treatment.
Authors: Keskinkilic Merve , Yalcin Femin , Gozmen Tolga , Ellidokuz Hulya , Yavuzsen Tugba , Oztop Ilhan
Published: June 2023

e16092

Background: We aimed to reveal the prognostic value of inflammatory-nutritional prognostic score (INPS), which is a new scoring system created by using frequently used immune-nutritional markers, as a biomarker, on nutrition and immune status in patients with locally advanced GEJ and gastric cancer. Methods: Patients who were treated in Dokuz Eylul University Medical Oncology Department between 2010-2022 years and diagnosed with locally advanced GEJ and gastric cancer and receiving NACT were included in this study retrospectively. We selected the most valuable biomarkers (Albumin, ABR, CRP, CAR, De-Ritis, HALP, MLR, NLR, PLR, PNI, SII) to develop INPS by the least absolute shrinkage and selection operator (LASSO) Cox regression model. A prognostic nomogram incorporating INPS and other independent clinicopathological factors was developed based on the stepwise multivariate Cox regression method. The retained features with nonzero coefficients were used to establish a novel INPS. The selected four biomarkers were used to construct the novel INPS for our patients. Results: Median follow-up time of 101 patients was 16.7 months (95% CI= 3.7-73.7), DFS was 20.5 months (95%CI= 16.2-24.8 ), OS was 36.6 months (95%CI=25.4-47.8). The 101 patients in the study were randomly assigned to train (n = 71) and test (n = 30) sets in a 7:3 ratio. Using the LASSO Cox regression model, four inflammatory-nutritional biomarkers (INB) with nonzero coefficients, namely, PLR, DeRitis, PNI and LAR, of the 13 parameters were selected. The LASSO coefficient profiles of the 13 INB and 10-fold cross-validation for tuning parameter selection in the LASSO model were presented. The optimal cut-off values for these four biomarkers based on disease-free survival were determined using the Maximally Selected Rank Statistics. The respective cut-off values for PLR, DeRitis, PNI, and LAR were obtained to be 107.93, 1.75, 33.92, and 58.17. Both the patients in the Train set and the in the Test set were classified as low-risk (INPS score ≤ 1) and high-risk (INPS score >1) groups. There was a statistically significant difference in survival probabilities between low and high risk groups in both groups (respectively; p=0.009, p=0.029). A prognostic nomogram including INPS and other independent clinicopathological factors was developed. Conclusions: The search for biomarkers with prognostic value in GEJ and gastric adenocarcinoma receiving NACT continues. With this study, it has been shown for the first time in the literature that the new screening system, INPS, created with nutritional and inflammatory markers, can be used as a prognostic tool to predict disease-free survival in this patient group.
Outcomes of patients with oesophageal and gastric cancer in relation to their age and metropolitan residential status: A South Australian audit.
Authors: Kalapurackal Mathai Vinod , Bull Jeff A , Ullah Shahid , Karapetis Christos Stelios , Watson David I. , Bright Tim F , Roy Amitesh Chandra
Published: June 2023

e16095

Background: The incidence of oesophago-gastric cancer (OG) is increasing in the younger population. Factors such as obesity, chronic gastroesophageal reflux disease, smoking or a low dietary intake of fruits and vegetables may be responsible. Inferior survival outcomes are observed in younger patients with OG cancer. Survival rates can differ by geographic location, with poorer outcomes seen in remote and non-metropolitan regions. Aim To evaluate patient characteristics and outcomes of patients with gastro-oesophageal cancers in younger (<50 years) when compared to older (>50 years) patients and those residing in rural versus metropolitan areas in South Australia. Methods: Data from a tertiary referral hospital database in South Australia was retrospectively collected between 2012 to 2022. All patients with OG cancers were included. Baseline characteristics including demographics, risk factors for OG cancer, type and stages of disease, geographic location were collected. Survival outcomes of gastro oesophageal cancer patients <50 years and >50 years of age as well as those living in metropolitan versus rural locations were analysed. Statistical analyses were done using Pearson’s Chi square test, Wilcoxon rank sum test, Fisher exact tests and multivariate models. Results: Of the 937 patients in this audit, 6.5%% (n=61) were < 50 years of age, 72% men (n=670), median age of diagnosis was 72 years. There was statistically significant difference in the proportion of patients with different anatomical types of OG cancer based on age <50 versus >50 (P=0.02), while there was no difference in other baseline characteristics. Within the group of OG cancer patients <50 years, the frequency of gastric adenocarcinoma was more, when compared to older, >50 year group (55.7% vs 31.3%) whilst other cancer types such as GOJ adenocarcinoma (1.6% vs 6.3%), oesophageal squamous (8.2% vs 14.8%) and adenocarcinoma (34.4% vs 47.6%) were found less frequent in <50 year group compared to >50 year group. There were no significant differences observed in the 3 year (P=0.49), 5 year (P=0.61) and overall survival (2.29 vs 1.78 years, P=0.63) rates, in OG cancer patients < 50 years vs > 50 years old. Among 874 OG cancer patients with data available on geographic location, there was no significant differences observed between 3-year (P = 0.25), 5-year (P =0.27) or overall survival (1.72 vs 1.61 years, P = 0.3) in metropolitan versus rural patients in South Australia. Conclusions: In this audit gastric adenocarcinoma was more common in younger patients (<50 years of age). Young-onset OG cancer patients, when defined as aged younger than 50 years, had equivalent survival compared with their older counterparts and there were no significant differences seen in overall survival rates based on their geographic locations.
The impact of cancer prehabilitation on psychological outcomes and quality of life in patients with gastro-oesophageal cancer.
Authors: Halliday Laura , Moorthy Krishna , King Alex , Wynter-Blyth Venetia , Zamora Talaya Bernarda Zamora
Published: June 2023

e16096

Background: The impact of cancer on psychological health and health related quality of life (HRQoL) is complex and involves an interaction between pre-existing and cancer related psychological morbidity and symptoms. Factors such as self-efficacy are known predictors of recovery and HRQoL. The aim of this study is to assess the impact of multi-modal personalised prehabilitation on psychological outcomes and HRQoL in patients with curable oesophageal and gastric (OG) cancer. Methods: Data was collected for to all patients treated at a specialist centre between Jan 2016 and June 2018. Patients received multi-modal (physical, nutrition and psychological) prehabilitation from diagnosis into the post-operative period. Data on self-efficacy (SE), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and HRQoL (European Organization for Research and treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)) were collected at diagnosis (T1), completion of neo-adjuvant chemotherapy (T2) and 3 months after surgery (T3). A previously validated mapping function was used for predicting Euro QoL 5D-3L (EQ-5D-3L) from scale scores of the EORTC QLQ-C30 instrument to derive a EQ health utility (EQ-HU). Results: 137 patients underwent surgery. 86 patients underwent a thoracotomy in addition to a laparotomy. 107 patients received neo-adjuvant treatment. There was a significant improvement in SE [8.2 (6.2-9) to 8.8 (7.8-9.7); p = 0.002] and anxiety [5 (3-8) to 4 (2,7); p = 0.04] but not depression [2 (1-5) to 3 (1-5); p = 0.26] between T1 and T2. There were no differences between T2 and T3. There were no differences in global HRQoL and the individual scales of the EORTC QLQ-C30 between T1 and T2. However, between T2 and T3, there were significant reductions in global HRQoL [69.6 (18.2) to 64.7 (20.9); p = 0.04], physical [83.2 (18.2) to 70.9 (20.5); p = 0.001], role [79 (28.6) to 70.9 (28.3; p = 0.02], cognitive [84.2 (22.3) to 76 (23.3); p = 0.004] and social [79 (24.2) to 65.5 (26.1); p = 0.001] but not emotional functions [80.1 (21.4) to 79.5 (23.3); p = 0.67]. Mapping revealed that there was a significant improvement in EQ-HU from T1 to T2 [0.54 (0.52) to 0.79 (0.34); p = 0.001] and a significant fall from T2 to T3 [ 0.79 (0.34) to 0.58 (0.44); p = 0.001]. The minimum and maximum predicted values matched those of the validated mapping function used. Conclusions: This study shows that prehabilitation can have a significant impact on HU in patients on chemotherapy. Despite the well-recognised limitations of mapping, HU at baseline was comparable to that shown in previous research in OG cancer patients. Reduction in HRQoL seen after surgery was much less than previously published research, suggesting the protective effect of prehabilitation. Physical function deterioration, in particular was much less than anticipated.
Development of a postoperative nomogram to predict disease-specific mortality in gastric cancer: A competing risk analysis using variables the AJCC recommends be collected and registered.
Authors: Bando Etsuro , Ji Xinge , Kattan Michael W. , Koseki Yusuke , Furukawa Kenichiro , Fujiya Keiichi , Tanizawa Yutaka
Published: June 2023

e16099

Background: The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for individual risk prediction model for the era of tailored therapy. In several reports, gastric cancer postoperative nomograms for predicting overall or disease-specific survival have been described. The AJCC Precision Medicine Core introduced the attractiveness of disease-specific mortality (DSM) as an endpoint of risk model. This study aimed to develop the first pretreatment gastric cancer postoperative nomogram for predicting DSM that considers competing risks (CRs). Methods: The nomogram was developed using data of 2,501 patients with primary gastric cancer who are potential candidate for adjuvant chemotherapy based on NCCN guideline, and it was created with a multivariable Fine and Gray subdistribution proportional hazard regression model. Fifteen pathological or non-tumor-related variables (age, sex tumor location, tumor size, macroscopic type, histology, depth (pT), number of positive nodes (pN), number of negative nodes, location of positive nodes, lymphovascular invasion, lavage cytology (CY), tumor margin, serum CEA and serum CA19-9) were collected. They are recommended to collect and register by the AJCC. The model was validated internally using measures of discrimination (Harrell’s C-index), calibration and decision curve analysis. Results: In the development procedure, multivariable analysis for DSM selected 12 variables (age, tumor location, macroscopic type, histology, pT, pN, number of negative nodes, location of positive nodes, lymphovascular invasion, CY, tumor margin and serum CEA) for constructing the nomogram. The developed nomogram showed good discrimination, with a C-index of 0.802(0.786-0.817) that of the American Joint Committee on Cancer (AJCC) pathological stage was 0.714 (0.697-0.734). The calibration appeared to be accurate for the 5-year prediction. Compared with scenarios in which no prediction model was used for postoperative treatment decision making (i.e., assume all or assume none), the nomograms had a favorable net benefit across a wide range of decision threshold probabilities between 5-year DSM probabilities of approximately 5 and 95%. Conclusions: This new postoperative risk model accurately predicts DSM in gastric cancer and can be used for patient counseling in clinical practice.
Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature.
Authors: Dou Rongzhang , Irajizad Ehsan , Cai Yining , Fahrmann Johannes , Vykoukal Jody , Katayama Hiroyuki , Chen Yihui , Abdel Sater Ali Hussein , Pizzi Melissa , Ostrin Edwin J. , Yamashita Kohei , Ajani Jaffer A. , Hanash Samir M
Published: June 2023

e16101

Background: Gastric cancer is frequently diagnosed at an advanced stage and is associated with poor outcomes. A humoral immune response to tumor antigens in the form of autoantibodies occurs early during tumor development. Harnessing autoantibodies and corresponding antigens has potential for diagnostic and therapeutics applications. Methods: Plasma samples from gastric cancer patients were collected before treatment and from non-gastric cancer cases and healthy controls for identification and quantitative analysis of immunoglobin (Ig)-bound antigens using mass spectrometry. The Ig-bound antigens were pulled down with a Protein A/G column for analysis by mass spectrometry. A protein A/G plate capture enzyme-linked immunosorbent assay (ELISA) was developed to validate Ig-bound MS results. A combined biomarker panel was established based on a logistic-regression model and ROC analysis was used to assess panel performance. Results: From a total of 983 proteins identified from gastric cancer samples, four Ig bound proteins were found to be enriched in gastric cancer plasmas compared with healthy controls and plasmas from other cancer types which yielded an area under the curve (AUC) of 0.973 (95% confidential interval [CI] = 0.92-1.00) for gastric cancer discrimination with a sensitivity of 0.91 at 95% specificity. Enzyme-linked immunosorbent assay (ELISA) based data yielded a high correlation (r = 0.72, P = 0.0199) with Ig-bound mass spectrometry data. These four proteins were found to be highly expressed in gastric cancer based on TCGA transcriptomic data with concordant tumor cell proteomic data. Conclusions: Our data reveal a panel of plasma Ig-bound antigens associated with the development of gastric cancer with potential application for gastric cancer detection and monitoring and potential therapeutic relevance.
Early onset gastric cancer: An analysis of epidemiological and environmental risk factors.
Authors: Zarrinkhoo Erfan , Condamoor Shreya , Klingbeil Kyle D. , Park Joon , Jackson Nicholas , Chiu Victor Yundeh , Kadera Brian E.
Published: June 2023

e16103

Background: Gastric cancer is the fourth most common malignancy in the world and the second leading cause of cancer related deaths. Its overall incidence has decreased in recent years, but recent data suggests that its rate has actually been increasing specifically amongst younger adults. Emerging data suggests that it is the combination of biological risk factors and environmental triggers that are the cause for this increasing rate. There has been increased interest in studying early onset gastric cancer (EOGC) as a proxy for understanding the genetic alterations that lead to gastric cancer at any age. However, understanding the environmental factors that lead to the development of cancer at a younger age is an area of study that requires more exploration. In this study, we investigate the epidemiology, environmental risk factors and common presenting symptoms associated with early onset gastric cancer patients. Methods: This is a retrospective cohort study of 174 patients with newly diagnosed gastric adenocarcinoma at three safety net hospitals in Los Angeles between 2010 and 2022. The patients were divided into two groups, with an age cutoff of 45 years old for early onset gastric cancer. We compared the rates of smoking, alcohol use, infection with H pylori and gender between the two groups. The stage at time of presentation, rates of misdiagnosis, presenting symptoms, and mortality rates were also compared. Results: There was no statistically significant difference (p < 0.05) in rates of smoking, alcohol use, and H. pylori infection between the groups. However, patients with early onset gastric cancer were 10% more likely to be misdiagnosed, and 6% more likely to present with metastatic disease. They were also 16% more likely to be female, 17% more likely to be Hispanic, and 22% more likely to expire compared to patients older than 45. An analysis conducted on patients’ presenting symptoms indicated that hematemesis was much more likely to be associated with patients less than 45 to a statistically significant level (p = 0.035). Conclusions: Based on our findings, EOGC was more likely to be seen in females and Hispanic populations. Additionally, no risk factors were identified to be more closely associated with either cohort. EOGC patients were more likely to be misdiagnosed and therefore present with advanced disease, leading to higher rates of mortality. Further investigation into both genetic alterations and environmental factors associated with early onset gastric cancer is warranted, as this holds important implications for patients regarding diagnosis, treatment, and overall outcomes.
Donafenib combined with anti-PD-1 antibody and transarterial chemoembolization (TACE) as first-line (1L) treatment for unresectable/advanced hepatocellular carcinoma (HCC).
Authors: Zhou Jian , Yan Zhiping , Wang Zheng , Qiu Shuang-Jian , Yang Minjie , Zhu Kai , Yi Yong , Yu Lei , Sun Yun-Fan , Zhang Bo , Yu Jiaze
Published: June 2023

e16107

Background: Targeted drugs, immune checkpoint inhibitors and TACE are important non-surgical approaches to treat HCC. A triple combination of the three is under investigation. This prospective study was conducted to assess the efficacy and safety of donafenib combined with anti-PD-1 antibody and TACE as first-line treatment for unresectable or advanced HCC. Methods: Patients (pts) who had histologically or clinically confirmed HCC and with no prior systemic therapy, at least one measurable lesion per mRECIST, Child-Pugh score ≤7, and ECOG PS score 0-1 were enrolled and received donafenib 100 mg twice daily, anti-PD-1 antibody Q3W and on-demand conventional TACE. CT/MRI scans were performed every six weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival and safety. Results: A total of 30 pts were enrolled between Dec 2021 and Nov 2022. All pts had HBV-related HCC and baseline ECOG PS score of 0. Baseline characteristics are shown in the Table. As of 6 Feb 2023, eleven pts had discontinued the triple therapy. The median follow up time was 3.6 months (range, 1.8-13.4). The median number of on-study TACE sessions was 2 (range, 1-4). Among 29 efficacy evaluable pts, five pts had disease progression and no death occurred. The median PFS was not reached (95%CI, 2.4 months -NE). The 6-month PFS rate was 69.4% (95%CI, 34.5%-84.0%). Five pts had a complete response and 13 had a partial response (responders). ORR and DCR were 62.1% (95%CI, 42.3%-79.3%) and 86.2% (95%CI, 68.3%-96.1%) per mRECIST. The median time to response was 1.3 months (95%CI, 1.1-1.6). The median duration of response was not reached (95%CI, 3.4 weeks-NE). Four pts (1 with BCLC B, 3 with BCLC C) underwent successful surgical resection after a median treatment duration of 2.9 months (range, 1.8-3.3) and no recurrence was noted with a median of 5.9 months (range, 2.8-10.2) follow-up after hepatectomy. In the safety population (n = 30), any grade and grade 3 treatment-related adverse events (TRAEs) occurred in 15 (50.0%) and 7 (23.3%) pts with no grade 4 TRAEs or toxic death. Rash was the most common grade 3 TRAE (incidence: 13.3%) and led to treatment discontinuation in one pt. Conclusions: The triple combination of donafenib plus anti-PD-1 antibody and TACE showed promising efficacy and was well tolerated in pts with unresectable or advanced HCC. Clinical trial information: NCT05262959 . [Table: see text]
Costs and health care resource utilization (HCRU) for patients with advanced biliary tract (aBTC) cancer using administrative databases in Ontario, 2010 to 2020.
Authors: Seung Soo Jin , Saherawala Hasnain , Syed Iqra A. , Clouthier Derek L. , Shephard Cal S. , Chen Eric Xueyu
Published: June 2023

e16112

Background: Gemcitabine and cisplatin (gemcis) has been the standard of care for biliary tract cancer (BTC) for over a decade. One US model predicted the total lifetime cost of gemcis per patient to be $54,077 in 2020 CAD, although not all costs were considered. Our study objectives included quantifying updated costs and health care resource utilization (HCRU) associated with advanced BTC using real-world, population-level data from Ontario databases. Methods: We conducted a retrospective population-level study of patients diagnosed with recurrent or unresectable/advanced BTC (gallbladder cancer [GBC], intrahepatic and extrahepatic cholangiocarcinoma [IHC and EHC], Ampulla of Vater [AoV]) between January 1, 2010 and December 31, 2019. Follow-up data were available until December 31, 2020. HCRU and costs were calculated from the start date of first line (1L) of BTC-specific systemic therapies to death or the end of March 31, 2020 whichever occurred first. A macro-based costing methodology (GETCOST) was used and the mean cost per patient was reported in 2020 Canadian dollars (CAD). Mean cost per patient was calculated from diagnosis till the end of follow-up or death. The total number of HCRU-specific encounters for all years was divided by the number of BTC patients who used that HRCU in order to report the mean number of HCRU encounters (e.g., cancer clinic visits and inpatient hospitalizations). Results: Of 2,142 advanced BTC patients identified, 1,968 were diagnosed with non-AoV cancers (GBC, IHC, EHC or general BTC not otherwise specified) and 174 patients were diagnosed with AoV cancer. The mean cost per patient for all 1L-treated patients was $36,662 ($36,378 for non-AoV compared to $40,092 for AoV patients). By 1L-specific therapies, the highest mean cost per patient was for patients on gemcitabine and taxane combinations (gemtaxane) at $44,190, followed by gemcitabine and cisplatin (gemcis) at $34,507, then FOLFOX or FOLFIRI (fol) at $39,002 and carboplatin and gemcitabine (gemcarb) at $30,905. Untreated patients had a mean cost per patient of $42,136. The mean number of cancer clinic visits per patient per year during 1L ranged from 9.7 (untreated) to 13.7 (gemcis), while the inpatient hospitalizations per patient per year during 1L ranged from and 1.5 (gemcarb, fol and gemtaxane) to 2.4 (untreated). Conclusions: This study reports Canadian-specific, real-world costs and HCRU results of over 2,000 BTC patients. While cost results were stratified by type of BTC (AOV and non-AOV) and type of 1L therapies, the mean cost per patient ranged from $30,905 CAD to $44,190 CAD and HCRU results indicated substantial mean number of cancer clinic visits and inpatient hospitalizations. Thus, BTC patients incur a significant economic burden to the patients and Ontario public payer health system.
Regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in real-world practice in the United States (US): Final analysis of the prospective, observational REFINE study.
Authors: Kaseb Ahmed Omar , Cabrera Roniel , Iyer Renuka , Parikh Neehar , Kalman Richard , Ozgurdal Kirhan , Khan Javeed , Babajanyan Svetlana , Finn Richard S.
Published: June 2023

e16114

Background: In the observational REFINE study of regorafenib (NCT03289273) in pts with uHCC, treatment-emergent adverse events (TEAEs) were consistent with those reported in the global, phase 3 RESORCE trial (YJ Kim, ILCA 2022). Median overall survival (OS) in the overall global cohort of REFINE was 13.2 months; here, we present the final analysis of the US pt cohort. Methods: REFINE was an international, prospective, multicenter study that enrolled pts with uHCC for whom a decision to treat with regorafenib was made by the treating physician prior to enrollment, according to the local health authority approved label. The primary objectives were safety, including incidence of TEAEs (MedDRA v25) and dose modifications due to TEAEs. Secondary endpoints included OS, progression-free survival (PFS), and duration of treatment (DoT). Results: Of the 1005 evaluable pts from the global cohort, 65 pts (6%) were from the USA. In the US cohort, 78% were male, 69% had ECOG PS 0/1, and the population was younger than the global cohort (54% were aged <65 years vs 45% in the global cohort). The most common HCC etiology was hepatitis C in the US cohort (52% vs 24% in the global cohort) and the second most common was alcohol use (34% vs 25% in the global cohort). A lower proportion of US pts had extrahepatic spread compared with the global cohort (48% vs 59%), while a similar proportion had vascular invasion (both 34%). Use of prior immune checkpoint inhibitors was more frequent in US pts than in the overall global cohort (25% vs 10%). Most US pts (88%) had received prior sorafenib, consistent with the global cohort (96%). However, a relatively lower proportion of pts received regorafenib as a second-line therapy (71% vs 84% in the global cohort). Transarterial chemoembolization was the most common prior non-systemic treatment (42%). Median DoT was 3.1 months (range <0.1–24.6 months) in US pts vs 3.7 months (range <0.1–38.9 months) in the global cohort. TEAEs were reported in 91% of US pts and apart from a lower incidence of diarrhea and hand–foot skin reaction (HFSR) in US pts, incidences of TEAEs were comparable to the global cohort. In addition, TEAEs resulting in dose modification were relatively lower in US pts (38% vs 45% in the global cohort). Median OS in US pts was 11.4 months (95% CI 8.4, 18.0), similar to that reported for the global cohort (median OS 13.2 months [95% CI 11.6, 14.8]). Conclusions: The REFINE real-world study confirmed the safety and effectiveness of regorafenib in a broader population of pts than in the RESORCE trial. The findings remained consistent in US pts with uHCC. Clinical trial information: NCT03289273 . [Table: see text]
Clinical efficacy and safety of regorafenib for patients with recurrent hepatocellular carcinoma after hepatectomy: A real-world study in China.
Authors: Ni Yanbin , Zheng Jiaxi , Wang Yang , Li Zhao , Zhu JiYe , Gao Jie
Published: June 2023

e16119

Background: The therapeutic strategy for recurrent hepatocellular carcinoma (HCC) after hepatectomy is limited. There is a significantly unmet clinical need for effective treatment options for these patients. This study aimed to assess the clinical efficacy and safety of regorafenib alone or combined with a PD-1 inhibitor as a second or further-line treatment for patients with recurrent HCC after hepatectomy. Methods: Patients receiving regorafenib alone or combined with a PD-1 inhibitor in Peking University People’s Hospital from January 2019 to November 2022 were entered prospectively into a clinical database. Data were retrospectively analyzed. The major inclusion criteria were: histologically confirmed diagnosis of HCC; disease recurrence after radical hepatectomy; with tumor that cannot be re-resected; ECOG performance status score (PS) ≤2. Regorafenib was administered at the daily dose of 80-120 mg for more than 4 weeks. Progression-free survival (PFS) was the primary endpoint. The second outcomes included PFS, objective response rate (ORR), disease control rate (DCR), and the incidence of drug-related adverse events (AEs). CTCAE v5.0 was used for evaluation of AEs. Results: Twenty-two patients were enrolled with a median age of 59. The hepatic function of all patients was mildly impaired (Child-Pugh A). Among all patients, 36.35% of cases were enrolled in Barcelona Clinic Liver Clinic (BCLC) A and the remainder were in BCLC B. Eight cases (36.36%) received regorafenib in combination with PD-1 inhibitor therapy and 14 cases received regorafenib treatment alone. Among all patients, 86.36% of the cases were treated with regorafenib as second-line therapy. Five patients (22.73%) had extrahepatic metastasis. The median PFS and overall survival (OS) were 11.66 (±10.20) months and 16.92 (±10.21) months, respectively. The 3-month PFS rate was 100%. The 6-month and 12-month PFS rates were 75% (95%CI: 58.49%-96.70%) and 53.33% (95%CI: 34.88%-81.50%), respectively. The results showed a significant difference in median PFS between patients receiving regorafenib as second-line therapy and third-line therapy [12.30 months (95%CI: 4.25-20.36) vs 4.30 months (95%CI: 3.50-5.10); P<0.001]. In addition, there is a significant difference in median PFS between patients with extrahepatic metastasis and those without extrahepatic metastasis [5.20 months (95%CI: 3.48-6.92) vs 18.20 months (95%CI: 5.09-31.31; P=0.003)]. The ORR and DCR were 18.18% and 81.82%. The most frequent AEs were hand-foot syndrome (40.91%), pain (18.18%), diarrhea (13.64%), and hypertension (13.64%). Most AEs were grade 1 or 2, with only 1 case having grade 3 AE. Conclusions: Regorafenib alone or combined with a PD-1 inhibitor showed significant clinical efficacy in controlling the disease progression of recurrent HCC.
Efficacy and safety of donafenib combined with transcatheter arterial chemoembolization (TACE) and anti-PD1 antibody for the treatment of unresectable hepatocellular carcinoma (uHCC): A retrospective study.
Authors: Ge Naijian , Wang Xiangdong
Published: June 2023

e16120

Background: For unresectable hepatocellular carcinoma (uHCC), the efficacy of TACE monotherapy is not satisfactory. It has recently been reported that molecular targeted drugs combined with anti-PD1 antibody and TACE exhibit improved anti-tumor efficacy compared with monotherapy. Donafenib is a new generation of multi-kinase inhibitor which is approved as the first-line treatment for uHCC. This study aimed to explore the efficacy and safety of the combination therapy of donafenib, anti-PD1 monoclonal antibody and TACE in patients with uHCC. Methods: This was a single-center retrospective study, and involved patients with uHCC who received donafenib (200 mg po bid) combined with TACE and anti-PD1 monoclonal antibody or donafenib (200 mg po bid) combined with TACE at Shanghai Eastern Hepatobiliary Surgery Hospital from September 2021 to September 2022. All patients had at least one measurable lesion defined by mRECIST criteria. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) data of patients were collected and analyzed. Results: A total of 34 patients with uHCC were included and had a median age of 56 years (32–81 years). Of these patients, 3 (9%) were classed as BCLC stage B, 31 (91%) were BCLC stage C. All 34 patients were complicated with HBV infection. First-line treatment was administered to 24 patients (71%), among which 21 patients received donafenib combined with TACE and anti-PD1 antibody. 3 patients were treated with donafenib combined with TACE. The remaining 10 patients (19%) received second-line treatment, among which 7 patients were treated with donafenib combined with TACE and anti-PD1 antibody. 3 patients received donafenib combined with TACE. There were 14 patients (41%) with baseline AFP ≥400 ng/mL. At data cut-off, the median follow-up time was 5 months [95% CI: 3.42-6.58]. The best overall response rate (BOR) was complete response in 5 patients (14.7%), partial response in 13 patients (38.2%), stable disease in 10 patients (29.4%), and progressive disease in 6 patients (17.6%). The ORR was 52.9% (95%CI: 36.7–68.6%) and DCR was 82.4% (95%CI: 66.5–91.7%). The median PFS and median OS were not reached, the one-year PFS rate was 61.6% (95%CI: 38–78.7%), and the one-year OS rate was 83.1% (95%CI: 56.1–95.2%). The ORR (58%) and DCR (87.5%) of patients receiving first-line treatment were better compared with those of patients receiving second-line treatment (40% and 70%, respectively). Treatment-related adverse events (TRAE) were reported by 30 patients (88.2%), of which 7 patients (20.6%) had grade 3 TRAE. No grade 4 or 5 TRAE was reported. Conclusions: Donafenib combined with TACE and anti-PD-1 antibody exhibited encouraging efficacy and favorable safety profile in patients with uHCC.
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 .