bluuebunny/crossref_metadata_2025 huggingface dataset:
A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of patients in CheckMate 649: Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC).
Authors: Sugarman Ryan , Botteman Marc , Rusibamayila Nifasha , Nguyen Hiep , Lin Daniel
Published: January 2022

273

Background: In CheckMate 649 (CM 649), a randomized phase 3 trial of first-line treatment of advanced GC/GEJC/EAC, patients receiving nivolumab combined with chemotherapy (NIVO plus chemo) experienced superior overall survival (OS), progression-free survival (PFS), and maintained their HRQOL for longer duration versus chemo alone. In this analysis, we combined efficacy and HRQOL data from CM-649 into a single metric, quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST), to compare the net benefits of NIVO plus chemo versus chemo alone. Methods: In this analysis, OS was partitioned into three health states: time with grade 3/4 toxicity after randomization and before progression (TOX), time without symptoms of disease progression or toxicity (TWiST), and time from relapse or progression until death (ie, relapse, REL). Mean Q-TWiST was determined by multiplying each state’s duration with its utility (U) (U[TWiST], 1.0; U[TOX], 0.5; U[REL], 0.5). Relative Q-TWiST gains (calculated as Q-TWiST difference divided by chemo only OS) of ≥ 10% and ≥ 15% were defined as clinically important and clearly clinically important, respectively, based on established thresholds for clinical importance in prior Q-TWiST literature. Q-TWiST differences between treatments were calculated separately for patients whose tumors expressed PD-L1 CPS ≥ 5 and for all randomized. A threshold utility analysis assessed Q-TWiST differences by varying the TOX and REL utility between 0 and 1. Results: Compared with chemo alone, treatment with NIVO plus chemo was associated with Q-TWiST improvement of 2.8 months (95% CI 1.0-3.7; relative gain 20.6% [clearly clinically important]) in patients with PD-L1 CPS ≥ 5, and 1.8 months (95% CI 0.9-2.7; relative gain 12.7% [clinically important]) in all randomized patients, respectively. Threshold analyses showed that compared with chemo alone, treatment with NIVO plus chemo was associated with statistically significant Q-TWiST improvements exceeding minimum clinically important differences across the full range of TOX and REL utility values. Conclusions: Among previously untreated patients with GC/GEJC/EAC in CM-649, NIVO plus chemo significantly improved quality-adjusted survival compared with chemo alone. Q-TWiST gains with NIVO plus chemo were driven mostly by longer time patients experienced without symptoms of disease progression or toxicity (TWiST), and were associated with statistically significant and clinically meaningful gains. These Q-TWiST results provide further understanding of both a survival and quality of life benefit of NIVO plus chemo versus chemo alone, and may aid clinicians and patients in management decisions for this patient population.
Surgical, pathological and clinical features of advanced collorectal cancers with metastasectomy. "Onco-Colon Turkey Registry" real-life data.
Authors: Karadurmus Nuri , Yildirim Emre , Yalcin Suayib , Gumus Mahmut , Bilir Cemil , Cubukcu Erdem , Simsek Eda Tanrikulu , Arslan Cagatay , Dane Faysal , Celik Sinemis , Bilici Ahmet , Sendur Mehmet Ali Nahit , Oven Basak Bala , Isikdogan Abdurrahman , Turk Haci Mehmet , Karaca Mustafa , Karabulut Bulent , Ozcelik Melike , Cevik Duygu , Kefeli Umut ,   Onco-Colon Registry Group
Published: January 2022

299

Background: The contribution of metastasectomy to progression-free survival (PFS) and overall survival (OS) in patients (pts) with advanced stage colorectal cancer has been demonstrated in clinical trials. However, clinical trials may not represent the efficacy of treatment given to the whole population in daily practice, therefore evaluation of real-life data is needed. Methods: The demographic, pathological and clinical characteristics of 1064 RAS wild type pts were recorded in 28 centers in Turkey between January 2016 and March 2019 as part of the Onco-Colon Registry Program ( NCT04757311 ). Metastasectomy was performed in 169 patients (15.9%). In this study, pts with and without metastasectomy were compared in terms of demographic, histopathological and clinical features and treatment results. Results: Median follow-up time was 24 months(mos) (1-74), median age was 59 years (30-81). 32.5% of the pts were women. The proportion of pts with primary right colon was determined to be 16.8%. Synchronous metastasis was detected in 76.3% of those who underwent metastasectomy. Isolated liver metastasectomy was performed in 85.8% of the pts. It has been shown that 21.1% of the pts have MSI-H and 23.3% have a mucinous component. Metastasectomy was performed after conversion therapy in 54.8% of pts. In the patient group who underwent metastasectomy after medical treatment, the median time between the beginning of treatment and metastasectomy was found to be 7 mos (2-34). When the patient characteristics were compared, no significant difference was found between the groups with and without metastasectomy (p > 0.05). The median PFS (mPFS) was 13.5 mos in the group that underwent metastasectomy and 9.9 mos in the group that was not performed (p < 0.0001; HR: 0.63 (95% CI: 0.51-0.77). The median OS (mOS) was 47.3 mos in the group that underwent metastasectomy and 24.3 mos in the group without metastasectomy (p < 0.0001; HR: 0.36 (95% CI: 0.27-0.48). Conclusions: The significant contribution of metastasectomy on mPFS and mOS was shown in this reallife data based trial, where no difference was found in terms of general participation characteristics. In daily practice, prolonged mPFS and mOS emerges as pts who are followed-up radiologically at regular intervals from the beginning and who are appropriate for surgery have the chance of metastasectomy.
A phase II study of TAS-102 (FTD/TPI) in combination with ramucirumab (RAM) in advanced, refractory gastric (GC) or gastroesophageal junction (GEJ) adenocarcinomas (GEAs).
Authors: Mehta Rutika , Kim Richard D. , Martinez Jimenez Maria E , Blue Kirsten , Avriett Trenton , Kelbert Emily , Miller Kara , Ray Christopher , Valone Tiffany , Lee Woojoo , Kim Youngchul , Kim Dae Won
Published: January 2022

302

Background: The RAINBOW trial established the standard of care for treatment of metastatic GEAs with ramucirumab and paclitaxel after failure of fluoropyrimidine and platinum-based chemotherapy. While the combination achieved an objective response rate (ORR) of 28%, the incidence of any grade neuropathy was 46%. Therefore, there is an unmet need for novel treatment combinations that minimize the long-term toxicity of neuropathy. In a recently published Asian study, the combination of RAM+TAS-102 showed good disease control and acceptable toxicity profile. Methods: This was a single arm, single institution phase II trial using the combination of TAS-102 plus RAM in refractory GEAs. Patients (pts) received RAM 8mg/kg intravenously on day 1 and 15, and TAS-102 35mg/m2 orally twice daily on days 1-5 and days 8-12 every 28-day cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), ORR and safety profile. The trial was registered at www.clinicaltrials.gov (NCT03686488). Results: At data cut-off of August 15, 2021, 23 pts were enrolled. Baseline demographics are as follows: median age of 62 years (range: 23-74), median lines of prior therapy of 1 (1: 14 pts vs ≥2: 9 pts) and location of primary tumor (GEJ:19 vs GC: 4). 6-month OS rate was 56.2%. Median OS was 6.2 month (95% CI: 5.4-7.0) and median PFS was 4.9 months with median observation of 2.3 months. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had partial response (PR) and 15 (88%) had stable disease (RECIST v1.1). Eleven pts came off the study due to progression of disease, 8 for toxicities and 4 for consent withdrawal. Most common treatment-emergent adverse events (TEAEs) were diarrhea (39%), fatigue (39%) and hypertension (39%). Total 11 pts (48%) experienced grade 3 and 4 TEAEs, and most common Gr3 and 4 TEAEs were neutropenia (17%) and anemia (13%). Conclusions: The combination of RAM and TAS-102 showed very similar disease control rate as the study in Asia. The combination has now shown modest activity in advanced GEAs and should be investigated further now in the context of patients receiving immunotherapy-based treatment as first-line treatment. A randomized phase II study is currently enrolling patients with ramucirumab and TAS-102 or paclitaxel. Clinical trial information: NCT03686488.
Clinical outcomes and appropriate treatment strategies of locally advanced resectable cervical esophageal cancer.
Authors: Miyakoshi Jun , Honma Yoshitaka , Yokoyama Kazuki , Yamamoto Shun , Ishiyama Koshiro , Oguma Junya , Kashihara Tairo , Inaba Koji , Murakami Naoya , Igaki Hiroshi , Kato Ken , Daiko Hiroyuki
Published: January 2022

313

Background: Due to its rare nature, no standard treatment based on the randomized controlled trials for locally-advanced resectable cervical esophageal cancer (rCEC) has been established. Prognostic factors of locally-advanced rCEC are not also well evaluated. When considering the treatment for rCEC, larynx preservation (LP) is an important issue, as well as the prolongation of survival. This study aimed to clarify the clinical outcomes and prognostic factors on locally-advanced rCEC, and the appropriate treatment strategies focused on both LP and long-term survival. Methods: We retrospectively reviewed the medical records of rCEC patients treated with surgery or definitive chemoradiotherapy (CRT) at our institute from 2010 to 2020. This retrospective study was approved by the institutional review board of NCCH (2017-229). Results: A total of 123 cases were extracted as subjects, treated with surgery in 53 and CRT in 70. 1/3/5-year PFS and OS in all subjects were 52/40/36% and 84/60/56%, respectively. Univariate analysis indicated that clinical tumor depth might be a prognostic factor (T1 vs. T≥2, hazard ratio [HR]: 2.30, p=0027. in PFS; HR: 2.86, p=0.046 in OS). In the subjects with ≥T3 lesion (N=95) who usually require laryngectomy, both PFS (31.0 vs. 7.0 months, HR: 0.50, p=0.013) and OS (not reached vs. 25.0 months, HR: 0.28, p=0.005) were better in subjects treated with surgical approach than with CRT. Focused on the cases with ≥T3 lesion and initially treated with induction chemotherapy (N=33), the surgical approach also showed better clinical outcomes than the CRT approach (median PFS: 19.0 vs. 8.0 months, HR: 0.37, p=0.007; median OS: not reached vs. 18.0 months, HR: 0.18, p=0.007). Especially, subjects treated with induction chemotherapy followed by larynx-preserving surgery achieved better outcomes. Conclusions: This study indicated that clinical depth might be a significant prognostic factor in rCEC. A chemo-selection approach using induction chemotherapy might be a good strategy to achieve LP and improve survival outcomes in locally-advanced rCEC.
A novel circulating diagnostic and prognostic metagenomic signature in esophageal adenocarcinoma: Implications for precision oncology.
Authors: Pratama Muhammad Yogi , Omstead Ashten , Gillece John D , Gorbunova Anastasia , Kreft Rachael , Highlander Sarah K , Jobe Blair Anderson , Wang David H. , Kelly Ronan Joseph , Zaidi Ali Hussainy , Goel Ajay
Published: January 2022

336

Background: The high incidence of esophageal adenocarcinoma (EAC) remains a major clinical challenge as majority of these cases are diagnosed at advanced stages, with poor survival outcomes. Emerging evidence indicate intriguing associations between unique microbial profiles and cancer pathogenesis. More recent data also indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers. However, to date, no studies have systematically interrogated circulating metagenome profiling in EAC patients, particularly as non-invasive, early detection, surveillance and prognostic classifiers that may improve the current management paradigms. Methods: Metagenome sequencing was performed on 81 serum specimens collected from 51 EAC, 10 high grade dysplasia (HGD), 10 Barretts’s esophagus (BE), and 10 gastro-esophageal reflux disease (GERD) patients, respectively. Sequencing reads were classified using Bracken and MetaPhlAn3 to determine relative abundance between various classes. The Linear Discriminant Analysis effect size (LEfSe) method was performed to identify potential conserved and discrete microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build a model according to clinical and metagenomic classifiers to examine the diagnostic and prognostic potential of the identified metagenomic signature. Results: A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group – at the phylum, genus, and species level – with Lactobacillus sakei as the most prominent species in GERD vs. other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus ( L.Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris, but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI, 0.78 – 0.95), and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 [95% CI 0.66 – 0.92]) and an accompanying hazard ratio (HR) of 6.23 (95% CI, 2.65 – 14.46, P<0.001). Conclusions: This study describes unique blood-based microbial profiles in patients with GERD, BE, HGD, and EAC, that are further utilized to establish a novel circulating diagnostic and prognostic metagenomic signature in EAC.
Assessment of methylated BCAT1 and IKZF1 circulating tumor DNA as a potential diagnostic and prognostic biomarker in esophagogastic cancers.
Authors: Chan Mei Mei , Winter Jean M. , Pedersen Susanne Kartin , Roy Amitesh Chandra , Watson David I. , Hussey Damian , Young Graeme P. , Symonds Erin L.
Published: January 2022

348

Background: Esophagogastric cancers (EG cancers) are associated with high mortality and poor treatment outcomes due to advanced disease at diagnosis. Reliable non-invasive biomarkers are lacking for detection and prognostication. The aim of this study was to assess the clinical utility of methylated BCAT1 and IKZF1 circulating tumour DNA (ctDNA) for detection and prognosis of EG cancers. Methods: Blood samples were collected from patients diagnosed with either esophageal or gastric adenocarcinoma prior to commencing any treatment. DNA was extracted from plasma and analysed for methylation of BCAT1 and IKZF1, and ACTB as the reference gene, by multiplex qPCR. ctDNA positivity rates were assessed against cancer clinicopathological features using chi-squared tests and age-adjusted logistic regression with odds ratios (OR). Secondary outcome was overall survival after 12 months using cox-proportional hazard ratio (HR). Results: Ninety-seven patients (77/97 (79%) male; 70 (72%) with esophageal cancer and 27 (28%) with gastric cancer) were enrolled with median age 72 years (IQR = 61-79). Fifty-three (55%) were ctDNA positive. There was no difference between the ctDNA positivity rate of esophageal and gastric cancers (p > 0.05). Positivity was significantly associated with node positive tumours (N0 = 6/23 (20.7%), N1 = 5/10 (50%), N2 = 11/17 (64.7%), N3 = 3/4 (75%); p = 0.01) and depth of invasion (T1 = 0/9 (0%), T2 = 5/12 (41.7%), T3 = 17/36 (47.2%), T4 = 5/6 (83.3%), p = 0.049). ctDNA positivity was independent of history of GORD or Barrett’s disease (p > 0.05). There was a significant association between ctDNA and advanced stage disease (Stage I = 1/13 (7.7%), Stage II = 2/12 (16.7%), Stage III = 25/40 (62.5%), Stage IV = 25/32 (78.1%)), with stage IV cases having a 43-fold increased odds for a positive ctDNA result compared to stage I (OR = 43.1, 95%CI 4.7-392.0; p = 0.001). Patients testing positive for ctDNA had poorer overall survival outcomes compared to those testing negative (HR 4.23, 95% CI 1.84-9.68, p < 0.001). Conclusions: Our study demonstrates a potential role for methylated BCAT1 and IKZF1 ctDNA as a biomarker for the detection of EG cancers. The detection of ctDNA is significantly associated with poorer survival outcomes, with further studies warranted to determine whether ctDNA can be an independent predictor of survival. The integration of this ctDNA assay into clinical practice could further improve risk stratification, which may guide treatment strategies.
Genomic profiling as a response predictor of second-line treatment in advanced gastric cancer patients: Post-hoc analyses of two phase Ib/II trials.
Authors: Lee Choong-kun , Che Jingmin , Kwon Woo Sun , Park Sejung , Kim Hyo Song , Jung Minkyu , Chung Hyun Cheol Cheol , Rha Sun Young
Published: January 2022

351

Background: Targeted panel next-generation sequencing (NGS) is now actively performed in clinics to guide treatment decisions for advanced cancer patients. However, NGS profilings of advanced gastric cancer (AGC) do not provide relevant genomic biomarkers that could predict response to second-line treatment for AGC patients yet. Methods: Two paclitaxel-based phase Ib/II trials as a second-line treatment for AGC patients were included: GSK2636771 (PI3Kβ selective inhibitor) and paclitaxel for AGC patients with PI3K/Akt pathway alterations (PTEN trial, NCT02615730, presented at GI ESMO 2021) and nivolumab and paclitaxel for EBV-related, dMMR/MSI-H or PD-L1 positive AGC (K-umbrella-003 trial, NCT02951091, presented at AACR 2021). Pre-treatment tumor tissue samples from two trials were subjected to the in-house panel sequencing using CancerMaster Panel V2 (Kwon et al., GI ASCO 2021) that covers 524 genes for single nucleotide variants, 143 for copy-number variations, and 18 for fusions. Baseline genomic alterations were compared with each patient’s response and survival. Oncogenic signaling pathways were annotated manually according to previous reports. Tumor mutation burden (TMB) and Human leukocyte antigen (HLA) profilings were also performed. Results: Baseline tumor tissues from 54 patients (24 from PTEN trial, 30 from K-umbrella-003 trial) were available for NGS. In patients treated with GSK2636771 and paclitaxel, patients with PIK3R1 M326I mutation (n = 3) showed longer PFS (8.1 vs 2.8 months, P= 0.041), and patients without MYC Q48H (n = 13) showed better PFS (4.8 vs 2.6 months, P= 0.013). Genetic alterations in epigenetic pathway were found in 13 patients (54.2%) and showed worse PFS (2.8 vs 5.0 months, P = 0.04). In patients treated with nivolumab and paclitaxel, patients with RTK/RAS pathway alterations excluding deletions (n = 21, 70%) showed significantly longer PFS (4.1 vs 2.6 months, P = 0.0085), and patients with HLA-A02 supertype (n = 11, 36.7%) showed significantly longer PFS (12.4 vs. 2.7 months, P = 0.0068). In both studies, TMB-high was not related to the survival and there were no common predictive genomic alterations. Conclusions: We observed that specific NGS-based genomic alterations such as single gene mutations, altered signaling pathways and HLA genotyping were potential predictors of each targeted agent or immunotherapy as a 2nd line treatment of AGC patients, regardless of paclitaxel. Further correlative studies within AGC trials for exploring predictive biomarkers are warranted. Clinical trial information: NCT02615730; NCT02951091.
Systematic analysis of gene expression alteration of BIRC5/survivn in gastric cancer.
Authors: Wang Jianzheng , Li Qingli , Lv Huifang , Chen Xiaobing , Tu Shuiping
Published: January 2022

353

Background: BIRC5/survivin gene is a member of the inhibitor of apoptosis (IAP) gene family, which encode negative regulatory proteins that prevent apoptotic cell death. Abnormal BIRC5/survivin expression is associated with carcinogenesis. Methods: We used sequencing data from The Cancer Genome Atlas database，Oncomine database and GTEx database, analyzed BIRC5/survivin expression and gene regulation networks in gastric carcinoma (STAD).Kaplan-Meier plotter database was used to assess the BIRC5/survivin prognostic potential. ULACAN was used to further analyze the relationship between the expression of BIRC5/survivin and the clinical stage of gastric cancer, and the methylation data of the promoter region of BIRC5/survivin. LinkedOmics was used to identify differential gene expression with BIRC5/survivin and to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Gene enrichment analysis examined target networks of kinases, miRNAs and transcription factors. We investigated the correlation of BIRC5/survivin expression in gastric cancer with immune infiltration levels from TIMER database and TISID database. Results: We found that BIRC5/survivin is overexpressed in gastric cancer. The patient with high expression of this gene is associated with poor prognosis. The expression of BIRC5/survivin is positive with ERBB2 expression,TMB,MSI,MSH2,MSH6,PMS2.BIRC5/surviving expression is significantly positively correlated to tumor purity and has significant negative correlation with the immune cell infiltration level of B cells,CD8+T cells,CD4+T cells, Macrophage cells, Neutrophil cells and Dendritic cells. BIRC5/survivin expression is significantly positively correlated CD274，LAG3 and PDCD1. Our results show a detailed landscape map of BIRC5/survivin gene mutation in STAD. Our results showed the associations between BIRC5/survivin expression and six immune subtypes: C1 (wound healing); C2 (IFN-gamma dominant);C3 (inflammatory); C4 (lymphocyte depleted); C6 (TGF-b dominant) in STAD. Conclusions: Our results demonstrate that data mining efficiently reveals information about BIRC5/survivin expression and potential regulatory networks in gastric cancer, laying a foundation for further study of the role of BIRC5/survivin in carcinogenesis and tumor immunotherapy.
Improving survival prediction of patients treated with external beam radiotherapy for dysphagia in esophageal cancer using prediction models.
Authors: Kuijper Steven , Jeene Paul M. , van den Boorn Héctor G. , El Sharouni Sherif , Braam Pètra , Oppedijk Vera , Verhoeven Rob , Hulshof Maarten C.C.M. , Van Laarhoven Hanneke W.M.
Published: January 2022

358

Background: The recently published POLDER trial investigated the effects of external beam radiotherapy (EBRT) on dysphagia caused by incurable esophageal cancer. As the effects of EBRT were presumed not to be immediate, an estimated life expectancy of minimally three months was required for inclusion. However, nearly a third of the included patients died within three months. The aim of this study was to investigate if the use of prediction models could have improved the physician’s estimation of the patient’s survival, and thus the eligibility for EBRT treatment. Methods: Data from the POLDER trial (N = 110) were linked to the Netherlands Cancer Registry to retrieve additional patient, tumor and treatment characteristics. Two published prediction models (the SOURCE model and Steyerberg model) were used to predict overall survival for all patients included in the POLDER trial. Predicted survival probabilities were dichotomized (predicted deceased/alive at three months) and the positive predictive value, negative predictive value, sensitivity, specificity and the area under the curve (AUC) were used to evaluate the predictive performance. DeLong’s test was used to test the difference between the AUCs of the SOURCE and Steyerberg models for statistical significance. Results: In the POLDER trial, 35 patients were unjustly presumed to survive three months. Predicting survival at three months, the SOURCE and Steyerberg model had an AUC of 0.76 and 0.60 respectively. The difference between the AUCs of the models was significant (p =.017). Under optimal survival cut-off scores, SOURCE would have incorrectly predicted 16 patients to survive three months. For the Steyerberg model this was 22 patients. Furthermore, using SOURCE under these cut-off scores, seven patients were incorrectly predicted to not survive three months compared to 18 patients using the Steyerberg model. Conclusions: Results showed that the SOURCE and Steyerberg models could have improved survival predictions compared to clinical judgement alone. The SOURCE model was found to be a more useful decision aid than the Steyerberg model as it was more accurate. Accepting that a small proportion of patients are incorrectly predicted not to survive three months and are not considered for EBRT treatment, we recommend using the SOURCE model for patients that are considered for palliative treatment of dysphagia caused by esophageal cancer.
Adjuvant S-1 versus observation in curatively resected biliary tract cancer: A phase III trial (JCOG1202: ASCOT).
Authors: Ikeda Masafumi , Nakachi Kohei , Konishi Masaru , Nomura Shogo , Katayama Hiroshi , Kataoka Tomoko , Uesaka Katsuhiko , Yanagimoto Hiroaki , Morinaga Soichiro , Wada Hiroshi , Shimada Kazuaki , Takahashi Yu , Nakagohri Toshio , Gotoh Kunihito , Kamata Ken , Shimizu Yasuhiro , Ueno Makoto , Ishii Hiroshi , Okusaka Takuji , Furuse Junji
Published: January 2022

382

Background: Capecitabine is usually used for patients with curatively resected biliary tract cancer (BTC) in EU and US, but no clear survival benefit has been shown in phase III trials. S-1, an oral fluoropyrimidine derivative, has shown promising efficacy, with a mild toxicity profile, in patients with advanced BTC. The aim of this trial was to confirm whether adjuvant S-1 therapy might improve the overall survival (OS) in patients with curatively resected BTC. Methods: This open-label, multicenter, randomized phase III trial was conducted in 38 Japanese hospitals. Eligible patients were aged 20 to 80 years old, had undergone R0/R1 resection for histologically confirmed adeno(squamous) carcinoma of the extrahepatic bile duct, gallbladder or ampulla of Vater (T2-4, N0, M0 or T1-4, N1, M0) or the intrahepatic bile duct (T1-4, N0-1, M0) (7th UICC classification), and had an ECOG performance status (PS) of 0 or 1.The calculated sample size was 440 to detect hazard ratio for OS of 0.74 with one-sided alpha of 5% and a power of 80%. Patients in surgery-alone arm received no further anti-cancer treatment, while those in adjuvant S-1 arm received 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m2 twice daily for 4 weeks, followed by 2 weeks of rest. Primary endpoint was OS, and secondary endpoints were relapse-free survival (RFS), incidence of adverse events, and proportion of treatment completion. Results: A total of 440 patients (surgery-alone, n = 222; adjuvant S-1, n = 218) were enrolled from September 2013 to June 2018. The data cutoff date was June 23, 2021, and the median follow-up duration was 45.4 months. Of all randomized patients, OS was significantly longer with adjuvant S-1 than surgery-alone (hazard ratio [HR] 0.694, 95%CI, 0.514-0.935; one-sided p = 0.008; the 3-year OS, 67.6% [surgery-alone; 95%CI, 61.0-73.3%] and 77.1% [adjuvant S-1; 95%CI, 70.9-82.1%]). Adjuvant S-1 was also better for RFS (HR 0.797 [95%CI, 0.613-1.035], 3-year RFS, 50.9% [surgery-alone; 95%CI, 44.1-57.2%] and 62.4% [adjuvant S-1; 95%CI, 55.6-68.4%]). All preplanned subgroup analyses (PS, age, cancer type, cancer stage, R factor, and serum CA19-9) revealed favorable OS and RFS for adjuvant S-1 arm. The main grade 3-4 adverse events in adjuvant S-1 arm were biliary tract infection (7.2%), diarrhea (2.9%), appetite loss (2.9%), fatigue (2.9%), and the treatment was well-tolerated. Conclusions: Adjuvant S-1 therapy led to significantly longer survival than surgery alone and becomes the standard of care for resected BTC. Clinical trial information: UMIN000011688.
Real-world use of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis.
Authors: D'Alessio Antonio , Weinmann Arndt , Galle Peter R. , Fulgenzi Claudia Angela Maria , Bettinger Dominik , Bengsch Bertram , Vogel Arndt , Balcar Lorenz , Scheiner Bernhard , Navaid Musharraf , Naqash Abdul Rafeh , Personeni Nicola , Pressiani Tiziana , Sharma Rohini , Pinter Matthias , Cortellini Alessio , Rimassa Lorenza , Pinato David James
Published: January 2022

393

Background: Atezolizumab plus bevacizumab (A+B) is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). No evidence exists as to its use in routine clinical practice in patients (pts) with impaired liver function. Methods: This retrospective, multi-center observational study was conducted across 7 tertiary academic referral centres and collected 64 HCC pts consecutively treated with A+B. Efficacy outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of A+B commencement and overall response rates (ORR) and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors (RECIST, v1.1). Safety outcomes included treatment-related adverse events (trAEs) graded (G) according to CTCAE v5.0. Results: Of 64 eligible pts, 54 had BCLC C stage HCC (84%), secondary to hepatitis C cirrhosis (n = 24; 37%), hepatitis B (n = 10; 16%), and non-viral etiologies (n = 40; 47%). Liver function was classified as Child-Pugh (CP) A in 46 patients (72%), B7 in 7 (11%), B8 in 8 (12%), and B9 in 3 (5%). Patients were of performance status (PS) ECOG 0 (n = 39; 61%) and 1 (n = 25; 39%). Pre-treatment upper-gastrointestinal endoscopy was performed in 44 patients (69%), with gastro-esophageal varices found in 18 pts (40%) and graded as 1 (n = 12, 27%), 2 (n = 4, 9%) and 3 (n = 2, 4%) respectively. After a median follow-up of 6.8 months (m) (95% confidence interval [CI], 5.5-8.0), median OS (mOS) was 11.7m (95% CI, 6.2-17.3) whereas median progression-free survival (mPFS) was 6.97m (95% CI, 2.9-11.0). ORR and DCR were 26% and 62% respectively. TrAEs of any grade were documented in 43 pts (67%): 12 pts (18%) had trAEs of G≥3: 7 (11%) atezolizumab-related and 5 (8%) bevacizumab-related. Toxicity led to treatment discontinuation in 3 pts (5%). Compared to CP-A, CP-B pts achieved shorter OS (11.7m [95% CI, 10.3-13.2] vs 6.5m (95% CI, 3.5-9.5), p = 0.029) and PFS (9.1m [95% CI, 5.4-12.8] vs 2.3m [95% CI, 1.7-2.9], p = 0.001) with no differences in ORR nor in DCR. The rate of trAEs did not significantly differ across CP classes. Median OS was significantly longer in patients achieving a radiologic response (12.7m [95% CI, not reached] vs 11.0m [95% CI, 5.5-16.5], p = 0.04). Presence and grade of varices was not associated to bevacizumab-related trAEs. Conclusions: This study confirms reproducible efficacy and safety of A+B in routine practice. Despite inferior OS and PFS compared to CP-A, A+B was associated with similar tolerability and radiologic response in CP-B patients, warranting prospective evaluation of A+B in this treatment deprived population.
Contemporary real-world evidence in unresectable HCC (uHCC) patients treated with regorafenib in Taiwan: Interim results from the observational REFINE study.
Authors: Lin Shi-Ming , Hsu Chih-Hung , Jeng Long-Bin , Lin Yih-Jyh , Lee Ming-Yang , Lee Teng-Yu , Huang Yi-Hsiang
Published: January 2022

402

Background: The phase 3 RESORCE trial showed that regorafenib improved overall survival compared to placebo in uHCC patients (pts) who progressed on sorafenib. The characteristics of real-world pts are more diverse than those included in clinical trials. The global observational REFINE study was designed to evaluate the safety and effectiveness of regorafenib in pts with uHCC in a real-world setting. Methods: REFINE is an ongoing observational study of pts with uHCC who were treated with regorafenib in routine practice. The primary end point includes to assess treatment-emergent adverse events (TEAEs; NCI-CTCAE v4.03). Secondary endpoints include overall survival, progression-free survival, and tumor response. Tumor response and progression are assessed per investigator according to local standard. A planned interim analysis of 1008 pts in the global cohort has been reported (Lim, ILCA 2021). We describe interim results in pts from Taiwan. Results: A total of 137 pts were enrolled and 136 were valid for safety analysis (80% male). At study entry, median age was 65.5 years (Q1-Q3, 60-72); 51.5% pts had an ECOG PS 0 and 24.3% and 12.5% had an ECOG PS of 1 and, respectively (missing 11.8%); proportion of pts classified as Child–Pugh A/B/C were 46.3%/10.3%/0.7% (missing/not evaluable: 40.4%/2.2%). The initial daily regorafenib dose was 160 mg in 8% of pts and 120 mg/80 mg in 9%/78%; 5.1% started at 40 mg. 83.1% pts received regorafenib as a second line agent and 15.4% pts as third line or beyond. 132 pts had prior sorafenib treatment with last daily dose being 400mg in 53.8% of patients; 9 patients (6.6%) had received an immune checkpoint inhibitor. The most frequent TEAEs are shown (Table). Effectiveness results will be presented. Conclusions: The characteristics of real-world pts from Taiwan not only differ from those in the RESORCE trial but also from the global REFINE cohort, reflecting variation across countries. A higher proportion of patients from Taiwan initiated regorafenib at a lower dose. Clinical trial information: NCT03289273. [Table: see text]
The association of family history of primary liver cancer with cholangiocarcinoma: USA case-control study.
Authors: Eluri Madhulika , Hatia Rikita , Javle Milind M. , Hassan Manal
Published: January 2022

403

Background: The incidence of cholangiocarcinoma (CCA), particularly intrahepatic cholangiocarcinoma (IHC) has exponentially increased in the United States since 2007. While cholangiocarcinomas share some common characteristics, increasing evidence suggests that different subtypes of CCA have divergent tumor microenvironments, pathobiology and distinct epidemiologic features and risk factors. The correlation between family history of cancer and cholangiocarcinoma remains to be determined. This study aims to address the connection between positive family history of primary liver cancer and development of cholangiocarcinoma, including intrahepatic cholangiocarcinoma (IHC) and extrahepatic cholangiocarcinoma (EHC), in USA. Methods: At The University of Texas M. D. Anderson Cancer Center, we studied 429 patients with pathologically confirmed cholangiocarcinoma (308 IHC, 121 EHC) and 1,075 healthy controls. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the subjects’ relationship with the relative, and the age at which the relative was diagnosed. Results: Independent of hepatitis B virus (HBV) and hepatitis C virus (HCV), a family history of cancer was significantly associated with IHC and EHC, the estimated ORs and 95% CI were 1.6 (1.2-2.2) and 1.6 (1.1-2.5) for IHC and EHC respectively. Primary liver cancer in first-degree relatives was significantly associated with EHC development (OR 9.4 [95% CI, 2.9-30.7]). No significant association was observed for IHC, (OR 1.7 [95% CI, 0.5-5.9]). The prevalence of family history of primary liver cancer in first-degree members was recorded in 6.6% of EHC patients and in 1.6% of IHC patients. Multiple relatives with primary liver cancer were observed in 5 patients (4.1%) among EHC subjects but less common in IHC (1%). All estimated ORs were adjusted for age, sex, race, smoking, alcohol, Hepatitis virus infection, diabetes, and obesity. Conclusions: First-degree family history of primary liver cancer is associated with EHC development in USA independent of known risk factors for CCA. Further research exploring the genetic–environment interactions associated with EHC is warranted. Focused efforts in identifying the population at increased risk for developing EHC are necessary and may lead to new screening and surveillance strategies.
Effectiveness of transarterial chemoembolization combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma.
Authors: Cao Fei , Yang Yi , Si Tongguo , Luo Jun , Zeng Hui , Zhang Zhewei , Chen Yi , Zheng Jiaping
Published: January 2022

414

Background: Combination therapies have been explored for the treatment of hepatocellular carcinoma (HCC) with favorable results, including PD-1 inhibitors plus lenvatinib and transarterial chemoembolization (TACE) plus lenvatinib. However, triple therapy with TACE combined with lenvatinib plus PD-1 inhibitors has not been investigated for patients with unresectable HCC. This study therefore aimed to investigate the effectiveness and safety of TACE combined with lenvatinib plus sintilimab in patients with advanced HCC. Methods: A single-arm retrospective study based on medical records and imaging data from 60 patients diagnosed with HCC using noninvasive methods or biopsy at the Cancer Hospital of the University of Chinese Academy of Sciences and the First Hospital of Medical University between January 2019 and March 2021. Eligible patients had received lenvatinib 12 mg (bodyweight >60 kg) or 8 mg (bodyweight <60 kg) orally once daily 2 weeks before TACE. Subsequently, sintilimab was administered at a dose of 200 mg intravenously on day 1 of a 21-day treatment cycle following TACE. The TACE procedure was repeated 4-6 weeks later and the chemotherapy regimens used included oxaliplatin (75 mg/m2) and iodized oil mixed with epirubicin (30-50 mg/m2). Objective response rate (ORR) and duration of response (DOR) were the primary endpoints and were assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: The analysis included data from 52 patients; 86.4% were male, 76.7% were aged ≤65 years, 13.5% and 86.5% had an ECOG performance status (PS) of 0 and 1, respectively and 88.5% and 11.5% had a Child-Pugh score of A and B, respectively. All patients were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage B (25%) or C (75%) disease. After a median follow-up of 12.5 months (95% confidence interval (CI), 9.1–14.8), the ORR was 46.7% (28/60: complete response, n=4; partial response, n=24). Twenty-three patients had stable disease, and nine had progressive disease. The median DOR for confirmed responders was 10.0 months (95% CI, 9.0–11.0). The median progression-free survival and overall survival were 13.3 months (95% CI, 11.9–14.7) and 23.6 months (95% CI, 22.2–25.0), respectively. In total, 84.6% (n=44) of patients had adverse events (AEs) of any grade. The most common treatment-related AEs were fatigue (30.8%), hypertension (25.0%), diarrhea (19.2%), decreased appetite (23.0%), and palmar-plantar erythrodysesthesia (21.1%). Conclusions: TACE combined with lenvatinib plus sintilimab is a promising and tolerable therapeutic regimen for patients with unresectable HCC.
The influence of major hepatectomy on gemcitabine-based chemotherapy for advanced biliary tract cancer: An exploratory subset analysis of JCOG1113.
Authors: Okuno Tatsuya , Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Kataoka Tomoko , Ikeda Masafumi , Ozaka Masato , Sugimori Kazuya , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Sekimoto Mitsugu , Sano Keiji , Tobimatsu Kazutoshi , Katanuma Akio , Gotoh Kunihito , Yamaguchi Hironori , Ishii Hiroshi , Ueno Makoto , Furuse Junji
Published: January 2022

419

Background: JCOG1113 (UMIN000001685) is a randomized phase III trial in patients (pts) with advanced biliary tract cancers (BTCs) that shows the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) regarding overall survival (OS). Previous reports suggest that a history of major hepatectomy (MH) may affect dose intensity and adverse event (AE) frequency and reduce treatment efficacy in chemotherapy due to impairment of liver function and drug metabolism. We thus investigated whether a history of MH affects the frequency of AEs and treatment efficacy in recurrent BTC pts in JCOG1113. Methods: Among the 354 pts enrolled in JCOG1113, 76 recurrent pts with recurrence after surgery were included in this analysis. We compared the frequency of AEs, progression-free survival (PFS), and OS of GC vs. GS in pts treated with MH vs. non-major hepatectomy (NMH). Results: Of the 76 pts, 17 on GC and 13 on GS were included in the MH group, while 20 on GC and 26 on GS were included in the NMH group. The primary sites were only intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma in the MH group, and there were no differences between the groups regarding sex, performance status, biliary drainage, or site of recurrence. The hazard ratio (HR) of GS to GC for PFS was 0.74 (95% CI 0.35–1.56) in the MH group and 0.97 (95% CI 0.52–1.82) in the NMH group. The hazard ratio (HR) of GS to GC for OS was 0.99 (95% CI 0.418–2.36) in the MH group and 1.17 (95% CI 0.59–2.33) in the NMH group. The median PFS and OS for GS in the MH group were 12.2 months and 21.5 months. These were longer than the 6.8 months and 15.1 months in the original results for GS in JCOG1113. Regarding AEs, Grade 3-4 AEs, specifically neutrophil count decreased (73.1%/92.3%), platelet count decreased (3.9%/15.4%), and rash (7.7%/15.4%), were more common in MH pts than NMH pts on GS. On GC, AEs in the MH and NMH pts did not show any consistent trends. The relative dose intensities (RDIs) of gemcitabine (70.7%/62.5%) and S-1 (70.4%/54.5%) were lower in MH pts than NMH pts on GS. The RDIs of gemcitabine (67.4%/63.0%) and cisplatin (73.6%/65.0%) were slightly lower in MH pts than NMH pts on GC. Conclusions: For pts with a history of MH, some AEs increased, and the RDIs were lower, especially that of S-1 for GS. On the other hand, the HR for PFS suggests that GS may be more effective than GC in MH pts.
Clinical results of dynamic tumor-tracking stereotactic body radiotherapy with real-time monitoring for liver tumors using a gimbal-mounted linac: A multi-institutional phase II study.
Authors: Iizuka Yusuke , Hiraoka Masahiro , Kokubo Masaki , Sakamoto Takashi , Karasawa Katsuyuki , Murofushi Keiko , Nakamura Mitsuhiro , Matsuo Yukinori , Morita Satoshi , Inokuchi Haruo , Mizowaki Takashi
Published: January 2022

441

Background: Dynamic tumor-tracking (DTT) stereotactic body radiotherapy (SBRT) with real-time monitoring for liver tumors using a gimbal-mounted linac can decrease the normal liver dose and planning target volume (PTV) without sacrificing the target dose. We hypothesized that this method would yield excellent tumor control comparable to that by the conventional SBRT. We conducted a multi-institutional prospective phase II study to evaluate the safety and efficacy of DTT-SBRT for liver tumors (UMIN-CTR, UMIN000017886). Methods: The main eligibility criteria were as follows: (1) < 4 liver tumors; (2) technical difficulties with percutaneous ablation therapies, inoperable lesions, or patient refusal to undergo surgery; (3) Eastern Cooperative Oncology Group performance status of 0–2; (4) Child-Pugh score of ≤8; and (5) respiratory motion of ≥10 mm. The primary endpoint was the local control rate (LC) at 2 years (expected endpoint: > 90%), and the secondary endpoints were overall survival rate (OS), progression-free survival rate (PFS), and treatment-related toxicity. We performed DTT-SBRT with 40 Gy in 5 fractions prescribed to the PTV D95, and a maximum dose of 55−58 Gy using 7–9 static non-coplanar ports of the 6-MV beam was applied. The Kaplan-Meier analysis was performed to estimate the OS and LC. Treatment-related toxicity was scored according to the Common Terminology Criteria for Adverse Events v.4.0. Results: Forty-eight patients (48 tumors) were registered from four institutes and successfully treated between September 2015 and March 2019. Their median age was 74 years (range, 52–97). Thirty-nine tumors were hepatocellular carcinomas, and nine were metastatic liver tumors. The median tumor size was 5.8 ml (range, 0.7–64.1). At the time of data cutoff on March 31, 2021, the median follow-up period was 36.5 months (range, 3.0–62.4). The 2-year LC was 98.0%. Two-year OS and PFS were 88.8% and 55.1%, respectively. Recurrences were observed in 33 patients (68.5%). One patient (0.2%) had local recurrence, 30 (62.5%) developed new hepatic lesions outside of the irradiation field, and 9 (18.8%) had distant metastases. Grade 3 adverse events were observed in seven patients, including elevation of liver or biliary enzyme levels and hematopoietic adverse events. No treatment-related toxicity of grade 4 or higher was observed. Conclusions: Employing DTT-SBRT to treat liver tumors resulted in excellent LC with acceptable incidence of adverse events. This method will be a promising alternative therapy for patients who cannot receive surgery or percutaneous ablation therapy. To the best of our knowledge, this is the first phase II trial evaluating DTT-SBRT for liver tumors. Clinical trial information: UMIN000017886.
Downstaging radiotherapy and surgical transformation for initially unresectable or borderline resectable hepatocellular carcinoma: A phase II study.
Authors: Su Ting-Shi , Gong Wen-Feng , Zhao Chang , Liang Shi-Xiong , Li Le-Qun , Xiang Bang-De
Published: January 2022

442

Background: Downstaging radiotherapy provide patients with initially unresectable or borderline resectable hepatocellular carcinoma (HCC) a chance to receive conversion curative resection. This study intended to prospectively evaluate the efficacy and toxicities of downstaging radiotherapy for HCC with macroscopic vascular invasion. Methods: From March 2018 to May 2020, 30 HCC patients with macroscopic vascular invasion were prospectively treated with transcatheter arterial chemoembolization combined with radiotherapy (n = 24) or radiotherapy alone (n = 6). The primary study endpoint was overall survival (OS). The secondary study endpoints were progression free survival (PFS), downstaging success rate, and surgical conversion rate. Adverse events were assessed. Results: The follow-up time of the entire cohort was 24 months. The median OS of the entire cohort was 22.0 months, 12-, and 24- months OS was 60.0% and 47.8%, respectively. The median PFS was 13.0 months, 12-, and 24-months PFS was 53.3% and 27.0%, respectively. During downstaging window phase within 3-6 months, 22 patients were evaluated as downstaging success by clinical imaging. Among them, 9 patients underwent R0 radical hepatectomy and 13 patients refused surgical treatment, yielding a downstaging success rate of 73.3% (22/30 patients) and a surgical conversion rate of 30.0% (9/30 patients). Of the patients who underwent surgery, 4 patients (44.4%) experienced ≥ grade 4 postoperative complications, including 2 (22.2%) with gastrointestinal bleeding and 2 (22.2%) with bile leakage. Conclusions: For unresectable or borderline resectable HCCs complicated with macroscopic vascular invasion, high-dose radiotherapy-based treatment provided favorable downstaging efficacy, surgical conversion rate, and survival outcomes. Clinical trial information: ChiCTR1800015350.