bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA detection as a prognostic tool in patients with localized colon cancer: A systematic review and meta-analysis.
Authors: Do Quan , Katiyar Vatsala , Malloy Meghan , Sharma Vivek R.
Published: June 2023

e15629

Background: Current modalities for postoperative risk stratification in localized colon cancer are still suboptimal in guiding adjuvant chemotherapy (ACT) administration. In recent years, circulating tumor DNA (ctDNA) has emerged as a novel biomarker to identify patients at high-risk for recurrence following R0 tumor resection. In this meta-analysis, we aimed to assess the prognostic value of ctDNA detection on postoperative recurrence risk that in the future, with further study, may help guide ACT treatment. Methods: Electronic databases Pubmed, Google Scholar, and Embase were searched up to 31 January 2023. Patient data were extracted using the following inclusion criteria: stage I to III colon cancers, R0 resection, sufficient ctDNA data following surgery, and no other concurrent malignancy. Pooled relative risk (RR) and 95% confidence interval (CI) were estimated to assess ctDNA positivity on the risk of recurrence in patients having surgery only, patients having surgery followed by ACT, and all patients combined. Random effects model was implemented to account for inter-study variation. Study heterogeneity was detected using χ2 test and I2 coefficient, with I2 more than 50% indicating significant heterogeneity. All analyses were completed using RevMan 5, with p < 0.05 being statistically significance. Results: Fifteen studies with a total of 3411 patients (64.4±10.7 years old) were evaluated. In patients undergoing surgery only without ACT treatment, postoperative ctDNA-positive patients were at higher risk of recurrence compared to those with negative ctDNA (RR = 7.73, 95% CI: 5.73-10.42, p < 0.01, I2= 0%). In patients having surgery followed by ACT, postoperative/pre-ACT ctDNA-positive patients were at higher risk of recurrence compared to ctDNA-negative ones (RR = 5.25, 95% CI: 3.67-7.50, p < 0.01, I2= 19%); post-ACT ctDNA-positive patients were also at higher risk of recurrence (RR = 6.34, 95% CI: 4.12-9.78, p < 0.01, I2= 29%). When combining the two populations (surgery only and surgery followed by ACT), postoperative ctDNA-positive patients again have higher risk of recurrence (RR = 3.86, 95% CI: 2.63-5.67, p < 0.01, I2= 87%); after completing all treatments, ctDNA-positive patients continue to have higher risk of recurrence (RR = 7.02, 95% CI: 3.40-14.51, p < 0.01, I2= 94%). Conclusions: This meta-analysis shows that the presence of ctDNA post-surgery correlates with higher risk of disease recurrence. In localized colon cancers, ctDNA detection can be a valuable tool to identify high-risk patients who, regardless of pathologic stage, may be the most likely to benefit from ACT treatment. Additionally, patients with persistently positive ctDNA after completing ACT are at very high risk for recurrence and should require closer follow-up than current guidelines, along with consideration of enrollment in clinical trials of newer treatment strategies.
Immunotherapy in locally advanced and metastatic rectal cancer: A propensity score matched analysis of the National Cancer Database.
Authors: Horesh Nir , Emile Sameh Hany , Freund Michael , Garoufalia Zoe , Gefen Rachel , Zhou Peige , Nagarajan Arun , Wexner Steven D
Published: June 2023

e15633

Background: Immunotherapy has been increasingly used in cancer therapy. In rectal cancer, patients with high microsatellite instability (H-MSI) are candidates for immunotherapy, but there is little evidence on its effect on overall survival. Methods: A retrospective analysis of all patients with stage II-IV rectal adenocarcinoma in the US National Cancer Database (NCDB) between 2010 and 2019 was performed. Patients without data on whether or not they had immunotherapy were excluded. Propensity-score matching was used to adjust for baseline and treatment confounders and the cohort was divided into two groups: patients who received immunotherapy and matched controls. The primary outcome was overall survival. Secondary outcomes included 30-day readmission and 30- and 90-day postoperative mortality. Results: 5175/206,615 (2.5%) patients with rectal adenocarcinoma were treated with immunotherapy during the study period. Patients treated with immunotherapy were younger (58 vs 62 years; p < 0.001), more often male (64.4% vs 61.7%; p < 0.001) and had more private insurance (50.8% vs 43.4; p < 0.001) compared to controls. Patients treated with immunotherapy had more metastatic disease at presentation (clinical TNM Stage IV - 80.8% vs 23.3%; p < 0.001), presented with larger tumors (median: 5 vs. 4.2 cm; p < 0.001) and less often underwent surgery (33.7% vs. 69.9%; p < 0.001), radiation therapy (21.5% vs 57.4%; p < 0.001) and standard chemotherapy (38.1% vs 61%; p < 0.001). After matching, 488 patients were included in each group. Overall survival was significantly shorter in the immunotherapy group, with a mean survival of 56.4 months (95%CI – 53.03-59.86) compared to 70.5 months (95%CI – 66.15-74.92) in the control group (p = 0.004). Cox regression analysis of factors associated with overall survival demonstrated that, for the entire cohort, immunotherapy was associated with an increased mortality (HR 2.16; 95%CI: 2.09-2.24; p < 0.001). After stratifying based on clinical staging, immunotherapy was associated with improved overall survival in stage IV patients (HR 0.91, 95%CI 0.88-0.95; p < 0.001) but with lower survival in stage II (HR 2.38; 95%CI: 2.05-2.77; p < 0.001) and stage III (HR 2.43; 95%CI: 2.18-2.7; p < 0.001). Conclusions: Immunotherapy was associated with a modest increase in overall survival in patients with stage IV metastatic rectal cancer. However, overall survival was significantly lower in patients with Stage II-III disease when treated with immunotherapy.
A new approach to reduce toxicity and improve quality of life in colon cancer patients receiving adjuvant chemotherapy.
Authors: Orlova Rashida , Varankina Anna , Androsova Alexandra , Belyak Natalia P. , Kutukova Svetlana
Published: June 2023

e15649

Background: We investigated the possibility of using accompanying therapy with enterosorbent in CRC patients receiving adjuvant chemotherapy. Methods: 40 pts (62 years [54.0-68.5]) with CRC (II-III) after radical surgery were randomized in 2 groups (1:1). Patients in the group 1 received ACT (XELOX), patients in group 2 received XELOX and enterosorbent "Polysorb" 30 mg orally, daily from 16 to 20 days of the ACT cycle. Results: The use of an enterosorbent can significantly reduce the manifestations of gastrointestinal toxicity: vomiting (5.0% vs 35.0%; p = 0.018), diarrhoea (5.0% vs. 40.0%; p = 0.008), flatulence ( 25.0% vs 70.0%; p = 0.004), constipation (0 vs 20.0%; p = 0.035) and abdominal pain (15.0% vs 50.0%; p = 0.018). In group 2, already by the 2nd cycle, the median scores on the QLQ-C30 symptomatology scale amounted to 22.0 points [14.0-28.5] vs 29.9 points [23.0-33.0] in the control group (p = 0.0441). By the 3 cycle in group 2, the average score on the QLQ-C29 symptomatic scale was 13.0±5.2 points (95% CI 10.5-15.4) and was significantly lower than in the control group (18.0±7.8 points (95% CI 14.3-21.6); p = 0.0224). When assessing the general condition according to the results of the analysis of the QLQ-C30 questionnaire, in the control group of patients there was a significant decrease in the number of points already by the beginning of the 2nd cycle of ACT - before the start of cycle 2 of ACT(p = 0.0369) and cycle 4 of ACT (p = 0.0447). Score of EQ-5D in the control group, significant decreases before 2 (from 84.9±6.4 points (95% CI 81.9-87.9) to 80.5 [77.55-86, 5]) (p = 0.0477) and 3 cycle ACT (from 80.5 [77.55-86.5] to 77.0±4.7 (95% CI 74.7-79.2)) (p = 0.0170), as well as a decrease in patient satisfaction with their condition at the time of the start of the 4th cycle of ACT compared with the baseline visit from 84.9±6.4 points (95% CI 81.9-87.9) to 75.7 ±6.7 points (95% CI 72.3-79.0) (p = 0.0001). Conclusions: The use of an enterosorbent as an accompanying therapy in CRC patients receiving ACT can significantly reduce the manifestation of chemotherapy toxicity and improve the quality of life of patients.
The adjuvant oxaliplatin-irinotecan paradox.
Authors: Mackey James David , Young Peter , Preble Richard , Miles Brittany
Published: June 2023

e15655

Background: A pervasive pattern in oncology is that chemotherapeutic agents which achieve acceptance for adjuvant use are the ones that have shown superior efficacy in the treatment of metastatic disease. The greater the efficacy in metastatic disease, the greater the likelihood that adjuvant use will be statistically viable. Oxaliplatin is the exception to this, having paradoxically shown similar outcomes to irinotecan in metastatic colorectal cancer (CRC) but superiority in the adjuvant setting. In this study, the TriNetX research database was used to better evaluate the adjuvant efficacy of oxaliplatin use in real-world patients. Methods: The TriNetX research database was used for this study. The TriNetX platform provides access to anonymized medical record information on more than 91 million patients in 75 large healthcare organizations. Three cohorts of stage III colorectal patients were created for comparison, utilizing International Classification of Disease-10 (ICD-10) codes and medication codes provided in the TriNetX platform. All patients were required to have a diagnosis of colon cancer (C18) and lymph node involvement (C77), with the absence of any liver or lung metastases (C78.7 and C78.0, respectively). Adjuvant oxaliplatin use was identified by the presence of the oxaliplatin medication code within 9 months of CRC diagnosis. The adjuvant oxaliplatin cohort was compared to a cohort with no oxaliplatin exposure, identified by the exclusion of the oxaliplatin medication code for 12 months following CRC diagnosis. The cohorts were balanced for age, race, gender, and ethnicity. The endpoint of the comparisons was all-cause mortality at 5 years. Results: Adjuvant use of oxaliplatin was associated with a 2.3% absolute decrease in the risk of death at 5 years (risk ratio 0.88, 95% CI (0.79,0.97), p-value 0.01). See figure 1. Conclusions: This study shows that adjuvant use of oxaliplatin is associated with a 2.3% absolute survival advantage in stage III colorectal cancer patients. This small absolute benefit is likely why occasional retrospective analyses have been unable to replicate it. A controlled interrupted time series analysis from Huang, et. al. showed no benefit to adjuvant oxaliplatin in the stage III setting for Taiwanese patients. Such a small benefit may also explain why the ACHIEVE trial found three months of adjuvant oxaliplatin to be equivalent to six. When a benefit is very small, a shorter duration of treatment would be more likely to result in statistical equivalency than if the benefit was more substantial. [Table: see text]
Efficacy and safety of first-line immunotherapy for advanced gastric or gastroesophageal cancer: System review network meta-analysis.
Authors: Qin Qiong , Sun Yongkun , Yang Lin , Zhong Diansheng
Published: June 2023

e16014

Background: In advanced gastric or gastroesophageal cancer, a series of randomized controlled trials had investigated different first-line immunotherapy compared with chemotherapy. However, the optimal immunotherapy strategy is yet to be established. We compared the efficacy and safety of first line immunotherapy for patients with advanced, HER2-negative gastric or gastroesophageal junction cancer. Methods: We performed systematic review and a network meta-analysis (NMA) of immune checkpoint inhibitors (ICIs) monotherapy or combined with chemotherapy for gastric or gastroesophageal cancer with HER2 negative. We searched PubMed, Embase, Cochrane Central Register of Controlled Trails, ClinicalTrials.gov, and several international conference databases, from 1 January 2012 to 1 March 2022.Published and unpublished randomized controlled trials compared different first-line immunotherapy with chemotherapy were included. This study was registered in the Prospective Register of Systematic Reviews (CRD 42021291609) to ensure transparency. Results: We analyzed a total 5 studies including 5279 patients and involving 5 immunotherapies. In patients without programmed death-ligand 1(PD-L1) selection, ICIs combined with chemotherapy improved progression free survival (PFS) and overall survival (OS). Sintilimab plus chemotherapy provided the best OS benefit (HR=0.77, 95% CI 0.63-0.94) and the best PFS benefit (HR=0.64, 95%CI 0.53-0.77) compared with standard chemotherapy. Furthermore, pembrolizumab plus chemotherapy seemed to provide the best objective response rate (OR= 1.81, 95%CI 1.44-2.28). Pembrolizumab monotherapy was the safest first-line treatment for grade equal or more 3 AEs (OR= 0.09, 95% CI 0.06-0.14). Subgroup analysis showed that sintilimab plus chemotherapy was associated with the best OS in CPS PD-L1≥1 (HR=0.73,95%CI 0.59-0.91) and PD-L1 ≥10 (HR=0.56, 95% CI 0.41-0.77). Pembrolizumab monotherapy improved OS in PD-L1 ≥10 (HR=0.69, 95% 0.49-0.97). Conclusions: Our results indicate that Sintilimab combined chemotherapy were associated with the best PFS and OS for patients with advanced GC or GEJC with HER2 negative.
Efficacy and safety of anlotinib hydrochloride combined with nivolumab in the treatment of advanced upper gastrointestinal tumor as second-line or later-line therapy: The results of gastric cancer cohort.
Authors: Cui Yuehong , Yu Yiyi , Wu Jing , Li Qian , Liang Li , Wang Yan , Yu Shan , Liu Tianshu
Published: June 2023

e16015

Background: The upper gastrointestinal tumors, such as gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC), have high rates of incidence and poor prognosis in our country, lacking of efficient therapy after failure of first-line regimen. Despite available treatment, there are still huge unmet medical needs of second-line or later-line therapy for patients with GAC or ESCC. Therefore, we will investigate the efficacy and safety of Anlotinib Hydrochloride (a multi-target tyrosine kinase inhibitor) combined with Nivolumab (PD-1 antibody) in GAC and ESCC. Methods: Patients with unresectable or metastatic GAC or ESCC who have failed standard therapy were treated by Anlotinib Hydrochloride 12mg/day orally for two weeks and Nivolumab 360mg every 3 week until the disease progression or intolerable adverse effects occurring. The study protocol was registered on ClinicalTrial.gov (NCT04503967,07/08/2020). The primary endpoint of this study was ORR (Objective Response Rate). The secondary endpoints were PFS (Progression-Free Survival), OS (Overall Survival), DCR (Disease Control Rate), and safety. Results: Gastric adenocarcinoma cohort would be reported only. From December 2020 to September 2022, 45 patients were enrolled in gastric adenocarcinoma cohort. There were 34 male patients and 11 female patients. The median age was 59 years. The percentage of gastric cancer patients with second-line and later-line treatment were 62.2% and 37.8%, respectively. 2 patients (4.4%) achieved complete remission (CR), 11 patients (24.4%) got partial remission (PR), and 15 patients (33.3%) got stable disease (SD). The ORR (CR+PR) was 28.9%, and DCR (CR+PR+SD) was 62.2%. Among 28 patients (62.2%) treated as second-line therapy, ORR was 32.1%, and DCR was 57.0%. As for later-line therapy of 17 patients, ORR and DCR were 23.5% and 70.6%, respectively. The median follow-up duration was 15.0 months (95% CI 8.17~21.83), then median PFS was 3.80±0.94 months, and median OS was 11.10±3.04 months. When the patients were treated as second-line therapy, median PFS was 3.0±0.97 months, and median OS was 14.50±3.89 months. Median PFS and OS in later-line patients of gastric adenocarcinoma were 3.80±1.30 months and 8.0±0.68 months, respectively. 36 patients (80%) had treatment-related adverse events (TRAEs). More than 10% of incidence rate included hypothyroidism (n=8), liver dysfunction (n=6), and rash (n=6). G3-4 of TRAEs were hypothyroidism (n=1), liver dysfunction (n=1), palmar-plantar erythrodysesthesia (n=1), rash (n=1), and hypophysitis (n=1). Conclusions: Anlotinib hydrochloride combined with Nivolumab showed effective clinical response and tolerable safety in second-line or later-line treatment of advanced gastric adenocarcinoma. Clinical trial information: NCT04503967 .
The prognostic value of metastasectomy among patients with gastric, pancreatic, and colorectal cancer accompanied by isolated liver metastasis: A SEER analysis.
Authors: Fahmawi Suhib , Abu heija Usama , Abdelhay Ali , Al-Ani Abdallah , Manthri Sukesh
Published: June 2023

e16026

Background: It is well acknowledged that the poor prognosis of gastrointestinal (GI) cancer is largely due to distant metastasis. It’s been reported previously that metastasectomy, particularly with liver metastasis in colorectal cancer patients, have survival benefit. Multidisciplinary management of distant metastatic cancer mandates the consideration of all treatment options, and in selected patients with hepatic metastasectomy can be performed with curative intent. There is no consensus on the ideal management strategy for synchronous disease. The purpose of this study was to analyze the prognostic value of metastasectomy in patients with certain GI cancers associated with isolated liver metastasis. Methods: A total of 14,204 patients who underwent primary site resection along with metastasectomy for isolated liver metastases from gastric, pancreatic, and colorectal were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2019. Patients younger than 18 years, and cases with missing information including age, gender, race, unknown stage, and unknown metastasis site were excluded. Cox-regression analysis estimated the prognostic value of metastasectomy, presented by hazard ratios (HR), among different GI cancers. Survival ratios were controlled for age, race, and gender. All analyses were performed on STATA v17. Results: Study sample included 3% of patients with gastric cancer, 4.2% with pancreatic cancer, and 92.8% were colorectal cancer patients. Incidence of metastasectomy was 19.9% among gastric cancer, 30.69% of pancreatic cancer and 25.76% of colorectal cancer patients. Cox-regression analysis demonstrated survival benefit for patients with gastric (HR 0.65, CI 0.45 - 0.94, p = 0.02), pancreatic (HR 0.51, CI 0.39 – 0.67, p < 0.001), and colorectal cancer (HR 0.58, CI 0.55 – 0.62, p < 0.001) patients undergoing metastasectomy. Conclusions: Aggressive approach with primary site resection along with metastasectomy for isolated liver metastases from gastric, pancreatic, and colorectal cancers significantly improved survival. Prospective data from evidence-based protocols is missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team. [Table: see text]
A retrospective cohort study examining the effects of anti–PD-1 antibody in combination with apatinib in patients previously treated for HER2-negative advanced gastric/gastroesophageal junction cancer.
Authors: Hou Xinfang , Li Shuai , Wu Chen
Published: June 2023

e16048

Background: Combining immune checkpoint inhibitors with vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) inhibitors are effective in treating a number of solid tumors; however, evidence in advanced gastric/gastroesophageal junction (G/GEJ) cancer is limited. Methods: This retrospective study included consecutive patients who received a programmed cell death protein 1 (PD-1) inhibitor plus the VEGFR-2 inhibitor apatinib, second-line or later to treat unresectable advanced or metastatic, histologically-proven, human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer in a single center between November 1, 2018 and March 31, 2021. Treatment was continued until the disease progressed or the toxicity became intolerable. Results: Data from 52 patients (median age 64 years; 38 men) were analyzed. The primary tumor site was the stomach in 29 patients (56%) and the GEJ in 23 patients (44%). The number of previous line(s) of therapy was one in 22 patients (42%) and two or more in 30 patients (58%). Liver metastasis was present in 22 patients (42%) and 33 patients (63%) had two or more metastatic sites. PD-1 inhibitors taken included camrelizumab (n=28), sintilimab (n=18), pembrolizumab (n=3) and tislelizumab (n=1), all given 200 mg every 3 weeks (Q3W), and toripalimab (240 mg Q3W) and nivolumab (200 mg every 2 weeks) in 1 patient each. The objective response rate was 15.4% (95% confidence interval [CI] 6.9–28.1), the disease control rate was 61.5% (95% CI 47.0–74.7). After a median follow-up of 14.8 months (range 11.8–23.5), median progression-free survival was 4.2 months (95% CI 2.6–4.8), overall survival was 9.3 months (95% CI 7.9–12.9). Grade 3–4 treatment-related adverse events occurred in 12 patients (23.1%). There was no unexpected toxicity or death. Conclusions: Combination therapy with an anti-PD-1 antibody and apatinib was effective in patients with previously treated, unresectable advanced or metastatic G/GEJ cancer, with a manageable safety profile.
Association of PIWI-interacting RNA-23210 with tumor metastasis in esophageal squamous cell carcinoma.
Authors: Peng Wei , Zhu Jinghua , Cao Guochun , Zhang Qin
Published: June 2023

e16060

Background: his study aimed to analyze the expression, clinical significance of PIWI-interacting RNA-23210 (piRNA-23210) in esophageal squamous cell carcinoma (ESCC) and the biological effect in its cell line by piRNA-23210 overexpression. Methods: Quantitative real-time RT-PCR (qRT-PCR) was used to analyze piRNA-23210 expression in 60 cases of ESCC and 60 cases of normal tissues to study the relationship between piRNA-23210 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress piRNA-23210 and then infect ESCC TE-1 cell line. qRT-PCR was used to detect the level of piRNA-23210. 3-[4,5-dimethylthiazol -2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis, cell cycle, and migration and invasion assays were also conducted as to the influence of the upregulated expression of piRNA-23210 that might be found on TE-1 cells biological effect. Results: The level of piRNA-23210 expression was found to be significantly lower in ESCC tissue than normal tissues (P < 0.05). Decreased expression of piRNA-23210 was significantly correlated with lymph node metastasis, clinic stage, and histological grade of patients with ESCC (P < 0.05). Meanwhile, loss of piRNA-23210 expression correlated significantly with poor overall survival time by Kaplan–Meier analysis (P < 0.05). The result of biological function show that TE-1 cell transfected piRNA-23210 had a lower survival fraction; higher percentage of the G0/G1 phases; higher cell apoptosis; significant decrease in migration and invasion; and lower cyclin D1, Bcl-2, and MMP-7 protein expression compared with TE-1 cell untransfected piRNA-23210 (P < 0.05). Conclusions: piRNA-23210 expression decreased in ESCC and correlated significantly with lymph node metastasis, clinical stage, poor overall survival, cell proliferation, cell cycles, cell apoptosis and migration and invasion in ESCC cell by regulating cyclinD1, Bcl-2, and MMP-7 expression, suggesting that piRNA-23210 may play important roles as a negative regulator to ESCC cell.
Phase I clinical trial using a unique immunotherapeutic combination of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of patients with advanced esophageal cancer.
Authors: Chen Size , Lin Yiguang
Published: June 2023

e16061

Background: Combining CAR-T with programmed cell death-1 (PD-1) inhibition may be a more efficacious approach for treatment of solid tumors. This clinical study was designed to assess the safety and tolerability of PD-1 knockout MUC1-Targeted CAR-T engineered Cells to treat advanced esophageal cancer. Methods: Patients with advanced esophageal cancer were recruited according to the criteria in NCT03706326. PD-1 gene knockout (KO) MUC1-targeted CAR-T cells were prepared by constructing MUC1-specific CARs using the SM3 scFv in patient-derived T-cells, and PD-1 gene KO was achieved in these CAR positive T cells using the CRISPR-Cas9 system. Efficiency and validation were confirmed by sequencing and flow cytometry. MUC1-CAR+/PD-1- KO engineered T cells at a starting dose of 5x107 were infused over 60 min. The dose was escalated to 5x109 cells. Following treatment, the safety and tolerability of dose of the therapeutic cells were assessed using CTCAE v4.0. Patients’ general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored at regular intervals. Circulating CART cells were checked regularly. Tumor size were examined by MRI/CT scans. Efficacy was also assessed. Results: A total of 9 patients (aged 48 to 80) diagnosed with esophageal cancer/esophageal squamous cell carcinoma (IIIb to IV), were included in this study. All participants received at least one cycle of CART cell treatment. Among the 9 treated patients, 4 received 1 cycle, other 5 received 2, 3, 4, 7 and 10 cycles, respectively. The most common adverse events (AE) were acute fever (8 patients, 38.0-40.5 C◦), chills (5 patients, occurred in the subsequent cycle of infusion), skin rash (4 patient). No grade 3-5 AEs were found, and no cytokine release syndrome (CRS) was observed. Of the 9 assessed patients, 6 had stable disease (SD) while 3 had progressive disease. All patients had significant symptom improvements after infusion. Circulating CART cells gradually declined after infusion; the number dropped down to approximately 25% in 4 months after one cycle treatment indicating the necessity of receiving more cycles. Patients who received multiple cycles of infusion showed long-term and steady SD status. Two patients who received a multiple cycle of CAR-T cells had an overall survival (OS) of 24 months. Conclusions: Our data suggests that the treatment of patients with advanced esophageal cancer with PD-1 disrupted MUC1-targeted CAR-T cells is safe and well-tolerated by all patients. No CRS and other serious EAs were observed throughout the study. The efficacy of this unique combined therapy is currently being assessed. Our limited data indicate that the OS of the patients extended significantly in the treated patients. Two out of 6 patients with an OS of greater than 24 months, an outstanding clinical outcome. Clinical trial information: NCT03706326 .
Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric adenocarcinoma (FRUTINEOGA): A multicenter, phase II study.
Authors: Wu Liucheng , Qin Yuzhou , Huang Mingwei , Long Di
Published: June 2023

e16063

Background: Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients (pts) with locally advanced GC, and SOX is the most common neoadjuvant regimen in China. Fruquintinib is a VEGFR inhibitor that blocks new blood vessel growth associated with tumor proliferation. It is a potent, highly selective small-molecule inhibitor of VEGFR-1,-2, and -3. The generally good tolerability in pts and fruquintinib’s low potential for drug-drug interaction suggest that it may be highly suitable for combinations with other antineoplastic therapies. We aimed to investigate the efficacy and toxicity of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC. Methods: It was a prospective, multicenter, phase II study in pts with stage III (cT3/4aN+M0) GC. Pts received 2 to 4 cycles of fruquintinib (5mg qd D1-14, Q3W) plus SOX (oxaliplatin 130mg/m2 D1, S-1 40-60mg bid D1-14 depending on body surface area (BSA), Q3W). Pts underwent D2 gastrectomy after neoadjuvant treatment. The primary endpoint was pathological response rate (pRR), and the secondary endpoints were disease-free survival (DFS), overall survival (OS), objective response rate (ORR), major pathological response rate (MPR), and R0 resection rate. Results: Up to February 3, 2023, 19 pts were eligible for the study. Median age was 62 years (29-73), 68.4% were male, and 21.1% were ECOG 1. Seven pts dropped out of clinical trial for AEs (2 pts), violation of treatment protocol (1 pt), staging error (2 pts), and refusal of surgery (2 pts). Twelve pts underwent surgery, 1 patient was found with peritoneal implantation, 11 patients underwent gastrectomy. Among the 11 pts, 9 pts achieved pRR (81.8%) and 3 pts achieved MPR (27.3%). The pathologic CR rate was 27.3% (3 of 11 pts). Moreover, 11 pts had curative intended operations and R0 resection rate was 90.9%. Among all the 19 pts, 16 pts received at least one dose of the combination treatment. A total of 2 pts had target lesions, 1 patient had complete response and 1 had partial response. Among the other 14 pts without target lesions, 1 (7.1%) had progressive disease with peritoneal implantation metastasis, and none had complete response. Furthermore, the most common TEAEs of grade ≥ 3 occurred in 19 pts were decreased appetite (21.1%), hypertension (21.1%), nausea (15.8%), vomiting (10.5%), oral mucositis (10.5%), fatigue (5.3%), diarrhea (5.3%) and respiratory infections (5.3%). There were neither new safety signals nor AEs inducing treatment deaths. Conclusions: The combination of fruquintinib and SOX as neoadjuvant treatment in patients with locally advanced GC is safe. The combination demonstrates promising evidence of anti-tumor efficacy in terms of pathological response. Clinical trial information: NCT05122091 .
Comparison of adjuvant capecitabine plus oxaliplatin (CAPOX) versus S-1 in patients with gastric cancer after gastrectomy based on the registry data base on the National Health Insurance Service (NHIS) database in Korea.
Authors: Maeng Chi Hoon , Kim Hoseob , Kim Mina
Published: June 2023

e16069

Background: The standard of care for locally advanced gastric cancer in Asia is still upfront gastrectomy with D2 lymph node dissection followed by adjuvant chemotherapy (AC). Both capecitabine plus oxaliplatin (CAPOX) and S-1 are accepted. Which of the two types of chemotherapy is better is still controversial. Methods: For this retrospective nationwide cohort study, data were obtained from the NHIS of Korea. As the NHIS is a single-payer healthcare system, it covers the entire population in the Republic of Korea and it also provides comprehensive information which contains demographic data, healthcare utilization, pharmaceutical prescriptions, and death for each patient. In study population, we included patients who received gastrectomy with a primary diagnosis of gastric cancer which were certified by international classification of disease (ICD) 10th codes of C16.x from January 1st 2013 to December 31th 2018. Survival outcomes of patients who received postoperative chemotherapy were compared based on S-1 (Arm S) vs. CAPOX (Arm C) as well as other relevant clinical variables such as age, sex, co-morbidity and completion of planned treatment. Results: During the study period, 98,556 patients were identified to have undergone both gastric cancer and surgery. After excluding ineligible subjects, a total of 6,602 patients were included in the analysis. Of these, there were 4,199 in Arm S and 2,403 in Arm C, respectively. After propensity score matching, final study population were identified 2,067 in each arm. Arm C showed statistically inferior survival (OS) compared to Arm S (5-year OS rate, 84.0% vs 90.0%, p < 0.0001). Disease-free survival (DFS) was also shorter in Arm C than Arm S (5-year DFS, 78.4% vs 86.1%, p < 0.0001). Age (65 ≥ vs. < 65) and incompleteness of the planned treatment had also significant negative effect on both OS and DFS. Charlson co-morbidity index (≥4 vs. 0-3) was not associated with the difference of OS or DFS. After adjusting with multivariable analysis, Arm C still showed worse OS (HR 1.609, 95% CI, 1.339-1.934, p < 0.0001) and DFS (HR 1.552, 95% CI, 1.333-1.807, p < 0.0001) compared to Arm S. Conclusions: Both S-1 and CAPOX showed excellent efficacy. This nation-wide cohort study suggests that S-1 can be a better option in some clinical situations.
A prospective analysis of robotic three-stage esophagectomy for carcinoma of the esophagus in a tertiary care cancer centre.
Authors: Bathala Udayee Teja
Published: June 2023

e16078

Background: This study is to evaluate the safety and technical feasibility of total robot-assisted three-stage esophagectomy in terms of: Completeness of surgery, margin status, lymph nodes harvested, learning curve, docking time and total operating time, and associated morbidity and mortality. Methods: It is a prospective non-randomised study from Nov 2016 to Nov 2022 with a total of 168 patients. Inclusion criteria: Histologically proven squamous cell carcinoma, adenocarcinoma of the intrathoracic esophagus surgically resectable (T1-3,N0 -1,M0); ECOG performance status: 0,1 or 2. Exclusion criteria: Carcinoma of cervical esophagus; patients unfit for general anesthesia; stage IV disease. Results: In a total of 168 patients, 52% had Squamous cell carcinoma and 48% had Adenocarcinoma; 8% had upper thoracic, 44.5% mid thoracic and 47% lower thoracic lesions. Mean docking time of 33 mins and mean operating time of 321 min. Average hospital stay of 7 days with average of 44 lymph nodes retrieved and mean blood loss of 280 ml. Intra operative complications of RLN injury in 2%, Thoracic duct injury in 1.6%, and Azygous vein injury in 1%.Post operative complications such as delayed gastric emptying in 3.5%, anastomotic leak in 2.9%, pleural effusion in 2.4%, wound infection in 0.6% and re-exploration in 1.7%. Conclusions: Robotic-assisted esophagectomy has its own unique benefits of very low conversion rates, short learning curve, good quality lymphadenectomy in supra-azygous and bilateral recurrent laryngeal nerve area, less painful with faster recovery even in aged patients with significant co-morbidities. Future RCT may confirm the lower incidence of major complications, and similar OS and DFS compared to open approaches.[Table: see text][Table: see text]
Phase II trial of terelizumab combined with radiotherapy of locally advanced unresectable esophageal squamous cell carcinoma: TREC trial.
Authors: Liu Changmin , Yu Zeshun , Hao Yanzhang , Wang Feng , Wang Zhenbo , Tian Lijun , Wang Yue , Ning Fangling
Published: June 2023

e16086

Background: Concurrent chemoradiotherapy (CCRT) is the standard therapy for locally advanced unresectable esophageal squamous cell cancer (ESCC)，However, some patients cannot tolerate or are unwilling to CCRT. The aim of this phase II trial was to assess the efficacy and safety of the tirelizumab combined with radiotherapy in patients of locally advanced unresectable ESCC. Methods: Key eligibility criteria were as follows: ESCC of clinical stage Ⅱ-Ⅳa; aged 18 to 90 years; cannot tolerate or are unwilling to CCRT; ECOG performance status 0 or 1; and performed radiotherapy: Involvement field irradiation, nodal GTV (GTVn) (regional lymphatic metastasis) radiotherapy dose 60Gy, the esophageal gross tumor volume (GTVt) radiotherapy dose 50Gy, if the gastroscope pathology is completely relieved, otherwise it is 60Gy. All patients registered before radiotherapy. The patient received concurrent therapy with tirelizumab (200mg every time, 3-week cycle), until the disease progresses or clinical benefits are lost (the longest time is 12 months). The primary endpoint was the esophageal gross tumor pathological complete remission rate (pCR). Results: Between 01 August 2021 and 31 December 2022, 31 patients were enrolled, and 27 completed radiotherapy and at least two times of tirelizumab treatment. Data cutoff date was 31 January 2023, median follow-up time among survivors after radiotherapy was 9 months (range 4-20). The esophageal gross tumor pCR rate was 66.7% (95% CI, 14.3%-52.3%) and treatment-related adverse events (TRAEs) of low severity (grade 1-2, 48.1%; grade 3, 7.4%; grade 4-5, no). No treatment-related mortality occurred. Two (7.4%) patients had tumor recurrence and two (7.4%) patients died (Infection and heart disease). The 1-year PFS rate, median PFS and median OS had not been reached yet. For locally advanced unresectable ESCC that can't receive CCRT, the combination of tirelizumab and radiotherapy shows promising efficacy and acceptable toxicity, providing a feasible and effective choice. The research of long-term survival analysis is under way. Conclusions: Concurrent radiotherapy with tirelizumab shows promising efficacy and controllable safety for patients with locally advanced ESCC who are unable or unwilling to undergo CCRT, and warrants further evaluation in larger studies. Clinical trial information: ChiCTR2100053182 .
Neoadjuvant tislelizumab plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC): Interim analysis of a phase 2 study.
Authors: Zhuo Na , Qiu Wei , He Jia , Li Li , Wang Qiang , Yu Shuangni , Liu Wei , Zhao Lin , Bai Chunmei
Published: June 2023

e16087

Background: Esophageal cancer (EC), as the sixth most frequently diagnosed cancer and the fourth leading cause of cancer death, poses a major health threat in China. Neoadjuvant treatment is recommended for resectable diseases with high recurrent risks; however, benefits with platinum-doublet chemotherapy are modest. Although the addition of tislelizumab, a anti-PD-1 antibody to chemotherapy has shown survival benefit in unresectable or metastatic EC, data are lacking to support such combination as a neoadjuvant modality. Here, we report the interim analysis of efficacy and safety of a prospective, phase 2 clinical trial evaluating tislelizumab plus chemotherapy as neoadjuvant treatment for locally advanced ESCC. Methods: Adults with clinical stage II-IVA (T3-T4 and/or node positive), potentially resectable ESCC, ECOG PS 0-1, and no known PD-1 expression were enrolled to receive tislelizumab (200mg) plus chemotherapy (docetaxel 75mg/m2 plus cisplatin 75mg/m2 or carboplatin AUC = 5 if CCr < 60ml/min) every 3 weeks for 4 cycles. Adjuvant tislelizumab up to 9 months were optional according to patients’ will. The primary endpoint was pathological complete response (pCR). Secondary endpoints include R0 resection, disease free survival (DFS), adverse events (AE), and biomarkers for predicting efficacy. Results: Between November 11, 2020 and Feburary 10, 2023, 28 patients with clinical stage III (n = 13) or IVA (n = 15) diseases were enrolled. 27 completed neoadjuvant treatment and 5 withdrew early because of disease progression (n = 2), serious AEs (n = 2) and bronchoesophageal fistula (n = 1). 21 patients underwent McKeown MIE and 20 (95.2%) acheived R0 resection. One patient was awaiting surgery. pCR (ypT0N0) was achieved in 33.3% (7/21) patients. According to the CAP tumor regression grading system, 3 (14.3%) cases were categorized as grade 1, 7(33.3%) were categorized as grade 2 and 4 (19%) were categorized as grade 3 in primary tumor. Most treatment related AEs (TRAEs) during neoadjuvant setting were mainly of grade 1 or 2. Grade 3 or 4 TRAEs occurred in 37.0% patients (10/27) and 14.8% (4/27) was considered immune-related. Surgical complications of any grade occurred in 4 patients (19.0%), 3 of which were grade 3. No grade 5 events were noted. 14 (66.7%) patients were able to continue adjuvant tislelizumab after surgery. Conclusions: Neoadjuvant tislelizumab plus chemotherapy has achieved encouraging pCR rate and tolerable safety activity in this study. Clinical trial information: ChiCTR2100043772 .
Comparison of efficacy and safety of neoadjuvant regimens for resectable esophageal squamous cell carcinoma: A meta-analysis.
Authors: Wang Ting , Cai Liyu , Guo Zefeng , You Peimeng , Liu Shengbo , Qiu Hongrui , Li Hao , Wu Shaowei , Zhou HaiYu
Published: June 2023

e16098

Background: Recent studies have demonstrated that preoperative neoadjuvant therapy in esophageal carcinoma can bring extra survival benefits compared to surgical resection alone or postoperative adjuvant therapy. There is still a lack of high-level evidence from large randomized controlled clinical trials to define the interval between neoadjuvant therapy and surgery, radiotherapy dose and target area plans after neoadjuvant treatment, therefore we adopted a meta-analysis to compare the efficacy and safety of different neoadjuvant treatment options in esophageal squamous cell carcinoma (ESCC) in these clinical studies. Methods: Articles were retrieved from PubMed, Cochrane, Embase, Web of Science databases and abstracts of ASCO and ESMO meetings in 2021-2022 by the terms esophageal cancer, neoadjuvant therapy, Inclusion criteria: a: Patients with excisable stage esophageal cancer. Histopathological confirmed squamous carcinoma of the esophagus; b: At least one reported primary outcome as follows: pathological complete response (pCR) rate; major pathological response (MPR) rate. Statistical analysis was performed on Stata 16.0 and R 4.0 with a significance level of 0.05. Results: A total of 39 clinical studies with a total of 2,434 patients, mostly male, were included, with a predominance of phase 2 trials. 16 neoadjuvant chemotherapy combined with immunotherapy (nICT), 2 neoadjuvant immunotherapy alone, 5 neoadjuvant chemoradiotherapy combined with immunotherapy (nICRT), 15 neoadjuvant chemoradiotherapy (nCRT), 1 neoadjuvant chemotherapy, 32 single-arm studies, and 7 randomized controlled trials. The overall neoadjuvant therapy pCR rate was 36% (95% CI: 32%-40%) and the overall MPR rate was 55% (95% CI: 47%-63%). The nICT pathological complete response rate was 31% (95% CI: 26%-36%), nCRT pathological complete response rate was 38% (95% CI: 32%-44%) and nICRT complete pathological response rate was 49% (95% CI: 39% -59%). Complete pathological response rates were 36% (95% CI: 31%-41%) for neoadjuvant immunotherapy (with immunotherapy) and 33% (95% CI: 13%-54%) for neoadjuvant immunotherapy alone. 26 studies had a mean R0 resection rate of 93%, with the majority of patients achieving R0 resection. Conclusions: From this Meta-analysis it can be concluded that nICRT has the best complete pathological response rate of all neoadjuvant treatments and nCRT has a better complete pathological reponse rate than nICT, but most of them are not phase 3 clinical trials, therefore more studies are needed to further clarify the benefit of neoadjuvant radiotherapy combined with immunotherapy in esophageal squamous cell carcinoma.
The impact of anti-EGFR therapy when added to first-line standard platinum-gemcitabine chemotherapy in advanced biliary tract cancers: A meta-analysis of randomized studies.
Authors: Findakly Dawood , Haddad Philip A.
Published: June 2023

e16109

Background: Biliary tract cancers (BTCs) represent the second-most common primary liver cancers. They are a heterogeneous group of tumors that include Intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder adenocarcinoma, and ampullary carcinoma. BTCs are usually diagnosed in an advanced stage and carry a poor prognosis. A better understanding of cancer biology has led to advances in targeted treatments in other cancers but remains an unmet need in BTCs. We conducted this meta-analysis to evaluate the efficacy of anti-EGFR therapy when added to the standard platinum-gemcitabine chemotherapy as first-line in patients with advanced BTCs. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of biliary tract tumors, randomized studies of first-line platinum-gemcitabine with and without anti-EGFR therapies, and studies that reported overall (OS) and progression free survival (PFS). A meta-analysis using the fixed effects and random effects models was conducted. Results: Four randomized studies with a total of 569 patients were included. Three studies were randomized phase 2 and one was randomized phase 3. Three studies used oxaliplatin and one used cisplatin in addition to gemcitabine as the standard combination. Panitumumab was used in two studies while cetuximab and erlotinib were used in one study each. The addition of anti-EGFR agent to first-line platinum-gemcitabine in advanced BTC resulted in a superior OS (HR = 0.72, 95%CI 0.61-0.85) and PFS (HR = 0.76, 95%CI 0.63-0.92). When the analysis was restricted to anti-EGFR monoclonal antibodies, their PFS benefit persisted (HR = 0.72, 95%CI 0.55-0.95), but their OS benefit failed to reach statistical significance (HR = 0.83, 95%CI 0.65-1.07). Conclusions: This is the first meta-analysis to show the addition of anti-EGFR agents to the standard first-line platinum-gemcitabine chemotherapy improves OS and PFS in advanced BTC.
PVR expression in tumor microenvironment of advanced hepatocellular carcinoma.
Authors: Lu Li-Chun , Lee Yi-Hsuan , Shao Yu Yun , Liu Tsung-hao , Cheng Ann-Lii , Hsu Chih-Hung
Published: June 2023

e16113

Abstract

Background: PVR (CD155)/TIGIT signaling has been investigated as a new immune checkpoint target in many cancers, including hepatocellular carcinoma (HCC). However, the expression and clinical significance of PVR, the ligand of TIGIT, have not been explored in the tumor microenvironment (TME) of advanced HCC. Methods: Patients with HCC who had adequate tumor tissues obtained at advanced stage were enrolled in the study. The membranous staining of PVR of tumor tissues, detected by immunohistochemistry (IHC), was semiquantitatively scored as IHC 0, 1, 2, or 3 if < 1%, ≥1% but < 5%, ≥5% but < 10%, or ≥10% of tumor cells (TCs) and tumor-infiltrating immune cells (ICs) were PVR positive. The correlation of PVR expressions and other clinic-pathologic factors was analyzed. Results: Sixty-seven patients were included in the study. Among them, 57 (85.1%) were male, 32 (47.8%) were aged over 60 years, 48 (71.6%) were HBV-reactive, and 23 (34.3%) had been treated with sorafenib before obtaining tumor tissues. Thirteen (19.4%) and 18 (26.9%) tumor samples showed positive PVR expressions in TCs and ICs, respectively (TCs, IHC 1/2/3: 3/3/7; ICs, IHC 1/2/3: 7/3/8). The expressions of PVR in TCs or ICs were not associated with sex, age, HBV/HCV infection, previous sorafenib treatment, or overall survival of the patients. Notably, in both TCs and ICs, the intensities of PVR expression were inversely correlated with PD-L1 expression for patients with at least IHC ≥1 in either PVR or PD-L1 (TCs, n = 26, r = -0.6966, p < 0.0001; ICs, n = 46, r = -0.4548, p = 0.0015). Conclusions: PVR expression can be identified in both TCs and ICs of TME of advanced HCC. The expressions of PVR and PD-L1 were inversely correlated. These findings may provide clinical implications for development of combination immunotherapy in advanced HCC. (This work is supported by grants from the Ministry of Science and Technology, Taiwan, MOST 110-2314-B-002-204-MY3). [Table: see text]