bluuebunny/crossref_metadata_2025 huggingface dataset:
Duloxetine (DL) in treatment of oxaliplatin-induced peripheral neuropathy (PN).
Authors: Chi Jeffrey , Fayyaz Fatima , Chung Su Yun , Jose Jyothi , Komorowski Anna W. , Dillon Maura , Shepherd Patnita , Gold Kenneth D. , Saif Wasif M.
Published: January 2021

195

Background: Oxaliplatin is commonly used to treat many GI cancers, especially colorectal (CRC), pancreatic (PC), and gastric (GC); however, peripheral neuropathy (PN) is the dose-limiting toxicity. Duloxetine (DL) is a second-generation selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of depression, anxiety, PN-associated with diabetes or ongoing pain due to medical conditions such as fibromyalgia. In this retrospective study, we evaluated the role of DL in reduction of oxaliplatin-induced neuropathy. Methods: Patients with GI cancers receiving oxaliplatin-based chemotherapy regimens from Nov 2016 to Nov 2019 were included. Patients with pre-existing PN from other etiologies such as diabetes, alcoholism, autoimmune disease, infections, hereditary, etc. were excluded. Neurological evaluations were performed serially before initiating DL and every 4 weeks thereafter according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. DL was given at 30 mg by mouth (PO) once daily and if tolerated after 3 days, was escalated to 60 mg once daily. Response was calculated to include number of patients with stable PN, improved PN, or no benefit. Adverse toxicities were graded. Results: 53 patients with median age of 53 years (range: 38 – 72) received DL for oxaliplatin-induced PN during treatment of GI cancers (CRC: 40%, PC:30%, GC: 10%, others: 10%). Improvement in PN from higher to lower grades was witnessed at 2 weeks in only 4 patients. At 4 week of DL, 3/53 (6%) patients improved from G3 PN to G2, 6/53 (11%) from G3 to G1, and 28/53 (52.8%) from G2 to G1, 14/53 (26%) and 2/53 (4%) had stable G3 and G2 PN respectively. At 8 week of DL, 10/53 (19%) of patients improved from G3 to G2, 3/53 (6%) from G2 to G1, 23/53 (43%) from G1 to G0, while 11/53 (21%), 2/53 (4%) and 4/53 (8%) remained stable at G1, G2 and G3 respectively. Overall DL resulted in a response rate of 89% and stable PN in 11%. 5 patients had to stop DL due to G3 drowsiness, insomnia, dry mouth and headache. Overall, DL was well-tolerated with majority of toxicities in G1-2 grade: dizziness (15%), drowsiness (11%), sexual side effects (11%), dry mouth (11%), insomnia (8%), headache (8%). In addition to PN, DL helped in improving depression in 50% of these patients and decreased the pain score in an additional 23%. Conclusions: DL resulted in a clinically significant improvement in PN-induced by oxaliplatin with manageable toxicity profile. Additionally, DL also improved depression and pain score. DL may be considered as an option in ameliorating PN in these patients, however, caution must be taken about DL and other drugs interaction. Our study warrants a prospective randomized trial to study the effectiveness of DL in treating oxaliplatin-induced PN. Moreover, cost effectiveness of DL in concurrently improving PN, depression and pain needs to be studied as well.
The impact of nutrition support in advanced gastric adenocarcinoma patients treated with chemotherapy.
Authors: Sugiyama Keiji , Shiraishi Kazuhiro , Motohashi Takuya , Onoda Shinpei , Noshibori Riko , Sato Mariko , Shimada Masaaki , Hirahsima Noboru , Kataoka Masato , Kitagawa Chiyoe
Published: January 2021

208

Background: Numerous studies have demonstrated how malnutrition and cachexia are associated with poor survival in advanced gastric cancer (AGC). The impact of nutrition support involving multidisciplinary specialists is unclear, particularly among patients with AGC being treated with chemotherapy. This study aimed to clarify the differences in patient characteristics and survival outcomes between patients receiving nutrition support (NS) and routine care (RC). Methods: We retrospectively analyzed 212 consecutive patients with AGC at a single institution between January 2015 and June 2020. Inclusion criteria were: histologically confirmed metastatic or recurrent gastric and adenocarcinoma and gastroesophageal junction patients treated with chemotherapy, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) in the entire cohort, patients with a positive Glasgow prognostic score (GPS) (graded as 1 and 2), and hypoalbuminemia (cutoff was 3.5 g/dl) were evaluated. Univariate and multivariate analyses were conducted to identify whether NS was an independent prognostic factor of time to treatment failure (TTF). Multivariate analysis included variables with p-values ≤0.1 in univariate analyses. Results: A total of 97 patients met the inclusion criteria with 67 (69%) and 30 (31%) patients classified into the RC or NS group, respectively. The median age was 71 years (range, 26-92). The median follow-up time was 8.4 months (range, 0.5-66). Patient characteristics revealed that NS was offered to patients with poorer prognostic nutritional index (PNI) (cutoff was 45, p=0.02), GPS positivity (p=0.01), and high neutrophil-lymphocyte ratio (NLR) (cutoff was 3, p=0.01). In the entire cohort, TTF in the RC and NS groups was 4.3 and 5.3 months (p=0.15), respectively. Among the patients with GPS positivity (graded as 1 and 2) and hypoalbuminemia, TTF in the RC and NS group were 2.3 and 5.0 months (p=0.05), and 2.3 and 5.3 months (p=0.02), respectively (Table). Variables with p-values ≤0.1 in univariate analyses for TTF were PS, NS, and prior gastrectomy. As per multivariate analyses, PS and NS were significant positive prognostic factors for TTF. Conclusions: NS was provided to patients with unfavorable clinical features. Among the AGC patients treated with chemotherapy, having GPS positivity or hypoalbuminemia seems to be a good indication for NS. [Table: see text]
Preoperative docetaxel, cisplatin, and 5-fluorouracil for resectable esophagogastric junction adenocarcinoma: A retrospective study.
Authors: Hirose Toshiharu , Yamamoto Shun , Oshima Kotoe , Hirano Hidekazu , Tsuda Natsuko Okita , Shoji Hirokazu , Iwasa Satoru , Honma Yoshitaka , Takashima Atsuo , Boku Narikazu , Oguma Zyunya , Ishiyama Koshiro , Daiko Hiroyuki , Kato Ken
Published: January 2021

209

Background: In Western countries, 5-FU plus leucovorin, oxaliplatin, docetaxel (DTX) (FLOT) is the standard perioperative treatment for resectable gastric adenocarcinoma and esophagogastric junction adenocarcinoma (EGJ-AC). Preoperative chemotherapy with DTX plus cisplatin and 5-FU (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there have been few reports on the safety and efficacy of preoperative triple therapy for resectable EGJ-AC. Methods: The subjects of this retrospective study were patients (pts) with histologically confirmed resectable EGJ-AC who received preoperative DCF chemotherapy (DTX 70 mg/㎡ and cisplatin 70 mg/㎡ on day 1, and continuous infusion of 5-FU 750 mg/㎡/day on days 1–5, every 3 weeks with a maximum of three cycles) at our hospital from Jan 2015 to Apr 2020. We evaluated the completion rate of >2 courses of DCF and R0 resection in all cases, and also examined histological response, progression-free survival (PFS), overall survival (OS), and adverse events during preoperative chemotherapy. Results: Thirty-two pts were included in this study, and the median observation period was 13.1 months (3.9–57.2). Characteristics were median age (range) 63 (42–80) years, PS 0/1 66/34%, clinical stage I/IIA/IIB/III/IVA/IVB (supraclavicular lymph node) 3/13/3/10/22/32/13%. Treatment completion rate was 84%. Histological response (grade 1a/1b/2/3) was obtained in 18/8/4/1 (58/26/13/3%) pts. Median PFS (95%CI) was 16.8 months (15.0–18.5), and median OS was not reached (3-year OS rate 73.8%). Grade >3 adverse events were observed in 20(63%) pts (neutropenia in 14 [44%], febrile neutropenia in 4 [13%]). No treatment-related deaths occurred. Conclusions: Preoperative DCF chemotherapy for resectable EGJ-AC was well tolerated. Further investigation is required to evaluate the long-term efficacy of this treatment strategy.
Comprehensive evaluation of genomic alterations in patients with gastric and gastroesophageal adenocarcinoma stratified according to TP53 mutation status.
Authors: Wood Anthony , Zhang Yonghong , Mo Qianxing , Cen Ling , Fontaine Jacques , Hoffe Sarah E. , Frakes Jessica M. , Dineen Sean P. , Pointer David T. , Pimiento Jose Mario , Mehta Rutika
Published: January 2021

238

Background: Gastric (GC) and gastroesophageal adenocarcinomas (GEA) are molecularly diverse. Molecular biomarkers of clinical significance have been identified that impact treatment decision making. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. However, TP53 mutations have not yet been confirmed as a target of therapeutic benefit. This study aimed to identify distinct genomic alterations that are dominant in TP53 mutated (MUT) versus wild-type (WT) GC and GEA in order to elucidate alternative therapeutic targets within these subsets. Methods: De-identified data for 3741 patients with GC and GEA was obtained from Foundation Medicine. The data obtained were age, gender, tumor mutational burden (TMB), and the distinct genomic alterations noted on DNA sequencing. The dataset was sorted by TP53 mutation status. Differences in mutation frequency were detected using the Fisher’s exact test of independence with a p-value of < 0.01 designated as the cutoff value for statistical significance. Results: The dataset consisted of 2946 GCs and 795 GEAs. TP53 mutations were present in 65.8% of specimens. 61.6% of GCs and 81.4% of GEAs were TP53 MUT positive (p = < .001). Median TMB score and the frequency of tumors with a TMB score > 10 was similar in both TP53 MUT and WT groups. 49 genes had statistically different mutation frequencies in TP53 MUT vs. WT patients. Top co-occurring genetic alterations in TP53 MUT patients included amplification and point mutations in MYC, CCNE1, MET, ERBB2, and EGFR. Amplification and point mutations in MDM2, CDK4, ARID1A, PIK3CA, and ERBB3 were the top co-occurring genetic alterations in TP53 WT patients. Conclusions: There was a high frequency of TP53 mutations in this group of GC and GEA patients, with a higher incidence of TP53 mutations identified in GEA samples. The mutational profiles of these tumors differed according to TP53 mutation status. These differences may be able to serve as the foundation for future clinical investigations.
Analytical and clinical validation of the TruCheck platform for diagnostic triaging of symptomatic cases suspected of colorectal cancer.
Authors: Akolkar Dadasaheb B , Patil Darshana , Fulmali Pradip , Fulmali Pooja , Patil Revati , Bendale Kiran , Adhav Archana , Patel Shoeb , Khan Shabista , Dhasarathan Raja , Rajan Vishal , Chougule Rohit , Shejwalkar Pradyumna , Ainwale Akshay , Garte Mohini , Sonawane Rahul , Purane Madhav , Chaudhari Yogeshwar , Sagar Prajakta , Nerkar Shubhangi
Published: January 2021

24

Background: Trucheck is a non-invasive approach for diagnostic triaging of symptomatic individuals who are suspected of Colorectal Cancer (CRC) and have been advised an invasive biopsy. Trucheck evaluates blood samples for presence of Circulating Ensembles of Tumor Associated Cells (C-ETACs: EpCAM+, Pan-CK+, CD45±) originating from a primary Colorectal Adenocarcinoma (CR-AD: CDX-2, CK-20, Muc2); such C-ETACs are unexpected in asymptomatic individuals as well as in individuals with benign Colorectal conditions. Methods: For Analytical Validation, spike-recovery analysis was performed using control cells / cell lines for EpCAM (SKBR-3), Pan-CK (SKBR-3), CD45 (PBMCs), CDX2 (CaCO2), CK20 (HCT15) and MUC2 (SW620) to determine the Sensitivity, Specificity, Accuracy, Limit of Detection, Linearity and Precision. Clinical Validations were performed using 15 mL blood samples from 587 participants. An initial Retrospective Clinical Pre-validation was based on blood samples from 350 known cases of CR-AD and 20 cases of non-CRC. The Prospective Clinical Validation was performed on blood samples collected prior to any invasive procedures from 217 symptomatic cases suspected of CRC. Results: Analytical Validation indicated 100% Sensitivity, 100% Specificity, 100% Accuracy, 90% Precision and significant linearity (R2≥0.98) for all ICC markers. Clinical Pre-validation indicated 84.9 % Sensitivity and 100% Specificity for CR-AD v/s non-CRC. In the Prospective Clinical Validation cohort, histopathological evaluation (HPE) of biopsied tumor tissue indicated benign Colorectal conditions in 10 cases and CR-AD 207 of the 217 suspected cases. Based on HPE as the standard, the Trucheck approach had 90.3% Sensitivity, 100% Specificity and 95.2% Accuracy. Conclusions: Symptomatic individuals suspected of CRC may benefit from the sensitive and specific non-invasive Trucheck approach. Individuals positive for CR-AD-specific C-ETACs can be prioritized for further clinical procedures while C-ETAC negative individuals can be considered for alternate diagnoses. The Trucheck approach can eliminate the need for (and risks associated with) invasive colon biopsies in a significant proportion of suspected cases and is especially useful where
Investigating chemopotentiation by low-dose fractionated radiation therapy for disseminated intra-abdominal gastric cancer.
Authors: Carrier France , Parekh Palak , Solano-Gonzalez Eduardo , Ma Xinrong , Tighe Kayla , Casildo Andrea , Zodda Andrew , Johnstone Christopher , Poirier Yannick , Mahmood Javed , Bhalla Kavita , Li Sheri , Lapidus Rena G.
Published: January 2021

242

Background: Treatment options are rather limited for gastrointestinal cancer patients whose disease has disseminated into the intra-abdominal cavity. There is currently no modality that has been shown to prolong survival of this patient sub-population. Here, we designed pre-clinical studies to evaluate the potential application of chemopotentiation by Low Dose Fractionated Radiation Therapy (LDFRT) for disseminated gastric cancer and evaluate the role of a likely biomarker, the Dual Oxidase 2 (DUOX2) enzyme. Methods: Nude mice were injected orthotopically with human gastric cancer cells expressing endogenous or lower levels of DUOX2 and randomly assigned to four treatment groups: 1; vehicle alone, 2; chemotherapy consisting of a modified regimen of docetaxel, cisplatin and 5’-fluorouracil (mDCF) for three consecutive days, 3; Low Dose- Whole Abdomen Radiation Therapy (LD-WART) (5 fractions of 15 cGy in three days), 4; mDCF and LD-WART. Blood was harvested at day 14 and 45 and cancer progression was evaluated by fluorescence imaging (Xenogen). Results: The combined regimen was well tolerated in all animals and led to DUOX2 upregulation, increased serum protein oxidation and reduced cancer progression in the DUOX2 positive tumors. Tumors expressing lower DUOX2 levels were more sensitive to chemotherapy but no additional benefit was obtained with LD-WART. The potential clinical significance of these findings is exemplified by a tumor microarray demonstrating that only about 46% of human gastric tumors expressed DUOX2. The molecular mechanisms underlying DUOX2 effects in response to the combined regimen include NF-kB upregulation and VEGF down regulation. Moreover, the combined regimen of mDCF and LDFRT was also effective on a Cancer Stem Cell (CSC)-Like subpopulation of mouse gastric cancer cells. Conclusions: Taken together these data suggest that DUOX2 could be used as a potential biomarker for patient stratification for chemopotentiation by LD-WART for positive tumors while chemotherapy alone would be more effective for DUOX2 negative tumors. The absence of added toxicity suggests that these cycles could be repeated.
Colonosight: Multitarget RNA-FIT assay for noninvasive detection of advanced colorectal neoplasia.
Authors: Barnell Erica Kay , Kang Yiming , Barnell Andrew Ross , Kruse Kimberly Ray , Fiske Jared , Pittz Zachary R , Khan Adnan , Holmes Faith L. , Heubner Thomas A , Griffith Malachi , Griffith Obi , Chaudhuri Aadel A , Wurtzler Elizabeth Marie
Published: January 2021

25

Background: Effective colorectal cancer (CRC) prevention and screening requires sensitive detection of all advanced neoplasias (colorectal cancer and advanced adenomas). Existing noninvasive screening approaches cannot accurately detect precancerous adenomas with high sensitivity. Here we describe a multi-factor assay (RNA-FIT test) that combines 8 stool-derived eukaryotic RNA (seRNA) biomarkers, patient demographic information (smoking status), and a fecal immunochemical test (FIT) to sensitively detect advanced colorectal neoplasias and other precancerous adenomas in a 1,305 average risk (45-75 age) prospective cohort. Methods: Average-risk patients undergoing colorectal cancer screening were prospectively evaluated with the RNA-FIT assay prior to an optical colonoscopy. RNA-FIT test results were generated using an ordinal regression model and results were compared to the colonoscopy findings. The model was initially assessed via 5-fold internal cross-validation of the training set and the ultimate model performance was assessed on a hold out testing set. Results: Of the 1,305 eligible patients recruited, 939 were included in the training set and 366 samples were reserved for the hold out testing set. When evaluating all 5 folds of the training set, internal cross validation attained a 61% sensitivity for advanced neoplasias (n = 69), 22% sensitivity for other adenomas (n = 279), 80% specificity for hyperplastic polyps (n = 155) and 86% specificity for no findings on a colonoscopy (n = 436). When employed on the testing set, the RNA-FIT test attained a 62% sensitivity for advanced neoplasias (n = 52), 27% sensitivity for other adenomas (n = 139), 78% specificity for hyperplastic polyps (n = 74) and 84% specificity for no findings on a colonoscopy (n = 101). Sensitivity for colorectal cancer and advanced adenomas with high-grade dysplasia / carcinoma in-situ was 100% in both the training set (n = 6) and hold out testing set (n = 5). Sensitivity for villous / tubulovillous adenomas was 65% in the training set (n = 23) and 60% in the hold out testing set (n = 15). Additional retrospective sample collection from patients with CRC is ongoing to further validate assay sensitivity for CRC. Conclusions: The RNA-FIT assay demonstrated clinically relevant detection of all advanced neoplasia, including early carcinomas, advanced adenomas, and other precancerous lesions. This assay could represent a noninvasive option to prevent colorectal cancer development through precancerous adenoma detection.
Efficacy and safety of nab-paclitaxel plus gemcitabine-cisplatin (GemCis/nab-P) in Korean patients with advanced biliary tract cancers (aBTC): Multicenter retrospective analysis.
Authors: Cheon Jaekyung , Lee Choong-kun , Sang Yunbeom , Kim Chan , Kang Beodeul , Chon Hongjae
Published: January 2021

274

Background: A recent phase II trial (NCT02392637) demonstrated prolonged survival by treatment with GemCis/nab-P in patients (pts) with aBTC. Further evaluation in real-world setting is necessary to measure the clinical outcomes of GemCis/nab-P in daily practice in Asian pts. Methods: This is a multicenter retrospective analysis of data from 3 institutes in Korea. Between September 2019 and August 2020, a total of 104 pts who received GemCis/nab-P for the management of aBTC were included in this analysis. Results: Median age was 64 years (range, 34-84), and 60 pts (57.7%) were male. GemCis/nab-P was used as the starting regimen in 60 pts (57.7%), 16 pts (15.4%) received GemCis/nab-P after failure of GemCis ± investigational drug (mainly immune checkpoint inhibitors), and 28 pts (26.9%) added nab-P to initial Gem/Cis without progressive disease. Baseline characteristics were as follows: Intrahepatic cholangiocarcinoma (CCC)/extrahepatic CCC/gallbladder cancer in 42 (40.4%)/33 (31.7%)/29 (27.9%); metastatic or recurred/locally advanced in 82 (78.8%)/22 (21.2%) pts. According to RECIST v 1.1, objective response rates (ORR) and disease control rate (DCR) were 30.8% and 81.8% of all pts, 33.4% and 88.4% in initial GemCis/nab-P, 28.6% and 73.8% in intrahepatic CCC, 36.3% and 96.9% in extrahepatic CCC, and 27.6% and 75.9% in gallbladder cancer groups, respectively. In nab-P addition group, while the ORR and DCR of pts without GemCis failure were 39.3% and 85.7%, those with GemCis failure were 6.3%, 50.0%, respectively. Median overall survival and progression-free survival were not reached, with a median follow-up duration of 3.3 months (95% confidence interval [CI], 2.9-6.7). The most common grade 3-4 toxicities were neutropenia (n=36, 34.6%), anemia (n=17, 16.4%), thrombocytopenia (n=10, 9.6%), and febrile neutropenia (n=9, 8.1%). In patients with locally advanced BTC (n=22), 5 patients (22.7%) were converted to resectable disease and underwent surgery. Conclusions: GemCis/nab-P showed consistent real-life efficacy and safety outcomes for Korean aBTC pts compared with those from the phase 2 trial. [Table: see text]
Contemporary real-world treatment patterns and outcomes of patients with advanced/metastatic hepatocellular carcinoma receiving second-line systemic therapy in the United States.
Authors: Gupta Arjun , Girvan Allicia C , Sheffield Kristin M , Chen Yongmei , Kirsch Kelly Rae , Gonzalez Gugel Elena , Peachey Jessica , Cui Zhanglin Lin , Yarchoan Mark
Published: January 2021

279

Background: Several therapies have recently gained regulatory approval in the United States (US) as second-line (2L) treatment options for patients with advanced unresectable or metastatic hepatocellular carcinoma (HCC). Treatment patterns and associated outcomes in a real-world population, especially in the contemporary era, remain understudied. Methods: This retrospective study utilized electronic health record data collected during routine patient care in outpatient oncology practices in the US. Adult patients diagnosed with advanced/ metastatic HCC between April 2017 and January 2020 were identified from the Concerto HealthAI database. Patients who survived at least one month from the end of first-line (1L) systemic therapy but did not initiate 2L therapy were classified as having received supportive care alone (SCA). Demographics, patient and disease characteristics, treatment patterns, and outcomes were described descriptively. Median overall survival (OS) from initiation of 2L therapy or end of 1L therapy for patients receiving SCA until death was estimated by the Kaplan-Meier method. Results: A total of 586 patients with advanced/ metastatic HCC were identified in the database. 330 patients received 1L therapy, and of those patients 63% (N= 207) received systemic 2L therapy (n= 105) or SCA (n= 102). At first diagnosis of advanced/ metastatic HCC, the median age was 64 years, and 86% were male. Of patients with ECOG status available at diagnosis (67%), 45% had ECOG status 0-1. The most common 1L agents prescribed were sorafenib (n= 126, 61%), lenvatinib (n= 28,14%) and sorafenib + nivolumab (n= 13, 6%) The most frequent agents prescribed in 2L were nivolumab (n= 44, 42%), sorafenib (n=18,17%), and lenvatinib (n=9, 9%). The median OS of patients receiving any systemic 2L therapy was 7.7 months (95% confidence interval 5.7-11.1) from time of receiving 2L therapy, whereas the median OS of patients receiving SCA was 5.0 months (95% confidence interval 3.3-7.1) from time of end of 1L therapy. Conclusions: In this contemporary national real-world cohort of patients with advanced/ metastatic HCC, a third of patients who received 1L therapy subsequently received 2L therapy. Next steps include investigating factors associated with non-receipt of 2L therapy, sequencing of therapies when multiple lines of therapies are received, and evaluating outcomes by type of agent received in 2L and beyond.
Anti-PD-1 antibody SHR-1210 combined with apatinib as adjuvant treatment in patients with hepatocellular carcinoma at high risk of recurrence after radical resection: Preliminary results from a multicenter, randomized, controlled phase II trial.
Authors: Zhao Hong , Zhao Jianjun , Jiang Li , Bi Xinyu , Qian Honggang , Du Shunda , Cai Jianqiang , Zhou Jianguo , Li Zhiyu , Liu Dongbin , Zhang Yubao , Zhang Ping
Published: January 2021

285

Background: There is no globally recognized standard adjuvant therapy for HCC after radical resection. Herein, we explored to evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib as adjuvant treatment versus hepatic arterial infusion (HAI) in HCC patients with high risk of recurrence after radical resection. Methods: This was an ongoing multicencer, randomized, controlled phase 2 trial. All HCC patients were Child-Pugh Class A, and confirmed as high risk of recurrence such as portal vein tumor thrombus (PVTT) involved in second-order branch or above, microvascular invasion (MVI) and microsatellite leisions. Eligible patients were randomly assigned (1:1) to receive SHR-1210 (200mg, q2w) and apatinib (250mg, q.d.) for 12 cycles, or two times of standard HAI treatments (epirubicin 80-100mg or epirubicin 50mg+oxaliplatin 50mg). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoints included safety and quality of life score (QoL). Results: From Jun 12, 2019 to Sep 15, 2020, 32 Chinese HCC patients (pts) (16pts in SHR-1210-apatinib group and HAI group, respectively) had been recruited. Full analysis (FAS) population contained 29 pts and intention to treat (ITT) population included 32 pts. The hadzard ratio for relapse or death with SHR-1210-apatinib as compared with HAI was 0.48 (95% CI 0.12-1.75; P = 0.2992) and 0.38 (95% CI 0.11-1.20; P = 0.0910) in FAS and ITT population, respectively, at date cutoff. Median RFS was not reached and 10.5 months in SHR-1210-apatinib group and HAI group, respectively. The average QoL score during treatment was 48.8 and 49.2 in SHR-1210-apatinib group and HAI group, respectively. The most common grade 3 or 4 adverse events occurred in SHR-1210-Apatinib were γ-glutamyltransferase (GGT) increase (18.75%), leukopenia (12.50%), neutrophil count decrease, alanine and aspartate aminotransferase increase (12.50%), while in HAI group were lymphocyte count decrease (7.69%), hemoglobin increase (7.69%) and GGT increase (7.69%). Conclusions: In HCC patients with high risk of recurrence after radical resection, SHR-1210 combined with apatinib was tolerable, and might offer a new promising choice superior to HAI for adjuvant therapy in HCC, further study is needed to reach the pre-defined primary endpoint. Clinical trial information: NCT03839550.
Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: An international cohort study.
Authors: Howell Jessica , Samani Amit , Mannan Binish , Hajiev Saur , Aval Leila Motedayan , Abdelmalak Rebecca , Tam Vincent C. , Bettinger Dominik , Thimme Robert , Taddei Tamar Hamosh , Kaplan David Edward , Seidensticker Max , Sharma Rohini
Published: January 2021

289

Background:The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing. The impact of NAFLD on overall survival (OS), treatment response and toxicity in patients with HCC treated with sorafenib is unknown. We examined the impact of NAFLD on OS and toxicity in an international cohort of patients receiving sorafenib. Methods:Clinical and demographic data were collected from patients consecutively treated at specialist centres in Europe and North America. The impact of NAFLD on OS, sorafenib-specific survival and sorafenib-related toxicity compared to other aetiologies of liver disease using multivariable Cox-proportional hazards and logistic regression modelling was assessed. Results:5201 patients were treated with sorafenib; 183 (3.6%) had NAFLD-associated HCC. NAFLD-associated HCC patients were more likely to be older women(median age 65.8 vs 63.0 years, p < 0.01 and 10.4% vs 2.3%, < 0.01), with a median BMI of 29.4. After controlling for known prognostic factors, no difference in OS in patients with or without NAFLD was observed(adjusted HR 0.94 (95% CI 0.76 -1.16), p = 0.57). NAFLD-associated patients had more advanced stage HCC when they commenced sorafenib (BCLC C/D 70.9% vs 58.9%, p < 0.01) and were more likely to be commenced on a lower starting dose of sorafenib (51.4 vs. 36.4%, p < 0.01). However, there was no difference in sorafenib-specific survival between NAFLD and other aetiologies(HR 0.99, 95% CI (0.85 – 1.16, p=0.92). Adverse events were similar between NAFLD and non-NAFLD HCC groups, including rates of ≥ grade 2 hypertension(6.3 vs. 5.8%, p = 1.00). A lower rate of severe hand foot syndrome was observed in the NAFLD population(3.8 vs. 12.4%, p = 0.03). Conclusions: OS in HCC does not appear to be influenced by the presence of NAFLD. NAFLD-associated HCC derive similar clinical benefit from sorafenib compared to other aetiologies.
Atezolizumab plus bevacizumab for unresectable or metastatic hepatocellular carcinoma: A cost-effectiveness analysis.
Authors: Wang Wenjun , Wang Jingjing , Zhang Xin , Wang Yikai , Shi Juanjuan , Jia Xiaoli , Dang Shuangsuo
Published: January 2021

295

Background: In May 2020, atezolizumab plus bevacizumab was approved by US Food and Drug Administration for patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy due to improvement in overall and progression-free survival compared with standard sorafenib treatment. However, because of the high cost of atezolizumab plus bevacizumab, there is a need to assess its value by considering both efficacy and cost. The aim of this study is to evaluate the cost-effectiveness of atezolizumab plus bevacizumab vs sorafenib for patients with unresectable or metastatic HCC from the US payer perspective. Methods: A partitioned-survival model was developed to compare health care costs and clinical outcomes of atezolizumab plus bevacizumab vs sorafenib in first-line treatment of unresectable or metastatic HCC over 6-year horizon. Treatment effects were extracted from the IMbrave150 trial. Health care cost and health utility data were obtained from published studies and databases. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio of the incremental cost to the incremental quality-adjusted life years (QALYs). One-way deterministic and probabilistic sensitivity analyses were used to examine model uncertainty. Additional subgroup analyses were performed. Results: Atezolizumab plus bevacizumab resulted in increase of 0.623 life-years, 0.484 QALYs and $158,781 per patient at the base case analysis. The ICER was $322,500 per QALY (95% confidence interval, $136,275 to $801,509 per QALY), with 0.5% and 4.1% chance of being cost-effective at a willingness-to-pay threshold of $100,000 and $150,000 per QALY, respectively. The ICER never went below $150,000 per QALY in the one-way sensitivity analyses and among patients of clinically relevant subgroups in the subgroup analyses. Conclusions: Atezolizumab plus bevacizumab is unlikely to be cost-effective compared with sorafenib in first-line treatment of patients with unresectable or metastatic HCC from the US payer perspective.
Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): Results from a phase I study.
Authors: Meric-Bernstam Funda , Hanna Diana L. , El-Khoueiry Anthony B. , Kang Yoon-Koo , Oh Do-Youn , Chaves Jorge M , Rha Sun Young , Hamilton Erika P. , Pant Shubham , Javle Milind M. , Raghav Kanwal Pratap Singh , Fortenberry Allison , Gray Todd , Woolery Joseph , Lee Keun Wook
Published: January 2021

299

Background: Treatment options are limited for patients with unresectable, locally advanced or metastatic BTCs progressing after first line treatment. Standard second line chemotherapy yields objective response rates (ORR) of < 10% and median overall survival of these patients is < 6 months. Human epidermal growth factor receptor 2 (HER2) overexpression/ amplification is observed in 5–19% of BTCs. Zanidatamab is a bispecific HER2-targeted antibody that has demonstrated durable single agent activity with good tolerability in a range of HER2-overexpressing cancers. Methods: In the expansion cohort of this phase I study (NCT02892123), the primary objective is to characterize safety and tolerability of zanidatamab and secondary objectives include evaluation of anti-tumor activity. This cohort includes BTC patients with centrally confirmed HER2 overexpression (immunohistochemistry [IHC] 3+ or IHC 2+/ fluorescence in situ hybridization [FISH]+), disease progression after standard of care therapy, and measurable disease per RECIST 1.1. Zanidatamab is administered at the previously identified recommended dose of 20 mg/kg every 2 weeks (Q2W). Tumors are assessed every 8 weeks (response confirmed at ≥ 4 weeks). Results: As of the data cutoff date (Jul 28, 2020), 20 patients (median age: 63 years [range, 42–78]) with BTC (11 gallbladder cancers, 5 intra- and 4 extra-hepatic cholangiocarcinomas) have been treated with zanidatamab. The median number of prior systemic therapies was 2.5 (range, 1–8), including five patients who had received prior HER2-targeted therapy (trastuzumab). Fourteen (70%) patients experienced zanidatamab-related adverse events (AEs), all of which were grade 1 or 2 in severity. The most common (occurring in ≥ 20%) zanidatamab-related AEs were diarrhea (n = 9) and infusion-related reactions (n = 6). A single treatment-related serious AE of grade 2 fatigue was reported in one patient. Among patients evaluable for response (n = 17), the confirmed ORR was 47% (n = 8; 95% confidence interval [CI]: 23, 72), the disease control rate was 65% (n = 11; 95% CI: 38, 86) and the median duration of response was 6.6 months (95% CI: 3.2, not estimable). Conclusions: Zanidatamab is well tolerated with promising and durable anti-tumor activity in patients with HER2 overexpressing BTC. Based on these data, zanidatamab is now being evaluated in an ongoing global Phase 2b study in patients with advanced HER2+ BTC that have progressed after treatment with a gemcitabine-containing regimen (NCT04466891). Clinical trial information: NCT02892123.
The impact of primary tumor sidedness on survival in early-onset colorectal cancer by stage: A National Veterans Affairs retrospective analysis.
Authors: Azar Ibrahim , Almasalmeh Nada , Esfandiarifard Saghi , Virk Gurjiwan , Kiwan Wissam , Shields Anthony Frank , Mehdi Syed Arzoo , Philip Philip Agop
Published: January 2021

31

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising. Left-sided colorectal cancer (LCC) is associated with better survival and response to therapy compared to right-sided colon cancer (RCC) in the metastatic setting. Current NCCN guidelines recommend the addition of EGFR inhibitors to KRAS/NRAS wild-type metastatic CRC originating from the left-side only. Whether primary tumor sidedness impacts survival in loco-regional disease and in EOCRC is of clinical interest. Methods: Data from the National VA Cancer Cube Registry was studied. 65,940 cases of CRC were diagnosed between 2001 and 2015. EOCRC (2,096 cases) was defined as CRC diagnosis at age <50 years. ICD codes C18 to C20 were used to delineate patients with RCC vs. LCC. RCC was defined as cancer from the cecum to the hepatic flexure (C18.0-C18.3), LCC from the splenic flexure to the rectum (C18.5-18.CRC; C19 & C20). Transverse cancer (C18.4), overlapping and unidentified sites (C18.8; C18.9) were excluded. Results: EOCRC is more likely to originate from the left-side (66.65% LCC in EOCRC vs. 58.77% in the whole CRC dataset). Overall, LCC has better 5-year OS than RCC in Stage I, III and better 1-year OS in stage IV (Table). Stage II RCC has better 5-year OS than LCC (RC 53.39% vs LC 49.28%). In EOCRC, there is no statistically significant difference between LCC and RCC in Stages I-III. Stage IV EOCRC patients with LCC and RCC have a 1-year OS of 73.23% and 59.84%, respectively. Conclusions: EOCRC is more likely than CRC to originate from the left side. In EORCRC patients, LCC is associated with better OS than RCC only in patients with metastatic disease. In the overall population, LCC is associated with better OS in all states except Stage II. The better prognosis of Stage II RCC might be due to the reported high incidence of MSI-high tumors in this subpopulation. [Table: see text]
Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?
Authors: Celsa Ciro , Cabibbo Giuseppe , Enea Marco , Battaglia Salvatore , Rizzo Giacomo Emanuele Maria , Cammà Calogero
Published: January 2021

324

Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.
Telotristat ethyl to enhance cytotoxic chemotherapy response in preclinical cholangiocarcinoma models.
Authors: Awasthi Niranjan , Schwarz Margaret , Schwarz Roderich E.
Published: January 2021

331

Background: Cholangiocarcinoma (CCA) is the second-most common primary liver cancer after hepatocellular carcinoma. It has a poor prognosis with a 5-year survival rate of 5-15%. The current standard first-line therapy for advanced unresectable CCA is a combination of gemcitabine and cisplatin (GemCis) chemotherapy that leads to a median survival of 6-12 months. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT) is an approved therapy for breast, NSCLC and pancreatic cancer. Elevated levels of serotonin have been reported in CCA that has protumorigenic activity. We tested the hypothesis that telotristat ethyl (TE), an inhibitor of serotonin biosynthesis, has antitumor activity in CCA and it augments GemCis and nab-paclitaxel response in preclinical CCA models. Methods: Tumor growth experiments were performed in mice subcutaneous CCA intrahepatic CCLP-1 xenografts, extrahepatic TFK-1 xenografts and patient-derived xenografts. Animal survival studies were performed using human CCA intrahepatic CCLP-1 cells in the peritoneal dissemination model in NOD/SCID mice. Results: In intrahepatic CCLP-1 subcutaneous xenografts, compared with controls, reduction in tumor growth was observed by TE (53%), GemCis (53%) or NPT (69%). The combination of TE with GemCis or NPT exhibited an additive tumor growth inhibition response, GemCis+TE (85%) and NPT+TE (90%). In extrahepatic TFK-1 subcutaneous xenografts, TE led to a significant reduction in tumor growth (51%), while GemCis and NPT reduced tumor growth by 37% and 56%, respectively. Again, an additive tumor growth inhibition effect was observed by the addition of TE to chemotherapy, GemCis+TE (67%) and NPT+TE (74%). In CCA patient-derived subcutaneous xenografts, GemCis caused the greatest tumor growth reduction (80%) followed by NPT (57%) and TE (40%). Combinations increased tumor inhibition further: GemCis+TE (95%) and NPT+TE (91%). Mouse survival in peritoneal dissemination xenografts was only marginally enhanced by TE (11%) or GemCis (9%) while NPT led to a substantial extension (60%). Interestingly, the combination of TE with GemCis or NPT demonstrated a further extension in mice survival: GemCis+TE (26%) and NPT+TE (68%). Conclusions: TE had antitumor activity and it enhanced chemotherapy effects in several CCA preclinical models indicating that this therapeutic combination has the potential to ameliorate clinical therapy for CCAs of different origin.
Results of biomarker analysis from phase II trial of nivolumab in refractory biliary tract cancer.
Authors: Tan Elaine , Kim Dae Won , Zhou Junmin , Schell Michael J. , Chung Vincent , Alese Olatunji B. , Kim Richard D.
Published: January 2021

338

Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients (pts) with refractory biliary tract cancer (BTC), suggesting the significant clinical benefit of nivolumab in selected pts and identification of potential predictive biomarkers. Here, we report outcomes from the biomarker analysis. Methods: Pre-treatment tumor samples were obtained and assessed for immunohistochemistry (IHC) with PD-1 and PDL-1 antibodies, mRNA sequencing (RNAseq), and whole exome sequencing (WES). Clinical efficacy was correlated with the molecular analysis. Prior cisplatin exposure was reviewed to evaluate the impact of cisplatin on the tumor mutational burden (TMB) and clinical outcome. Results: Among 46 pts who had tumor response evaluation, 31 pts received cisplatin prior to nivolumab, and 15 were cisplatin-naive. Pre-treatment tumor samples were assessed for IHC (n = 42), RNAseq (n = 11), and WES (n = 11) based on tissue availability. There was no statistically significant correlation between prior cisplatin exposure and clinical outcome. Among 42 available tumor samples, 18 (43%) expressed PD-L1 positivity ( > 1%), which was associated with a statistically significant prolonged progression free survival (PFS). Median PFS was 10.4 months for PD-L1 positive vs 2.4 months for PD-L1 negative (HR 0.23, 95% CI 0.10-0.51; P < 0.001), while there was no statistically significant correlation between PD-1 expressing tumor infiltrating lymphocytes and clinical outcome. There was also no statistically significant difference in TMB of cisplatin-exposed (n = 8) vs. cisplatin-naïve tumor samples (n = 3) (9162, SD = 150 vs. 8898, SD = 806, p = 0.62). In comparing the group with prolonged disease control of at least 16 weeks (n = 4) to those with rapid disease progression (n = 7) who had mRNA sequencing performed, levels of AC005609.1, FAT3, TMEM151A, ADARB2, FAM153A were all significantly upregulated (p < 0.01), while levels of CLCA1, MUC2, IGHV3-43, SWORA6, and CRISP3 were all significantly downregulated (p < 0.01). Conclusions: Prior cisplatin exposure did not lead to statistically significant differences in clinical outcome or TMB in advanced BTC pts treated with nivolumab. However, PD-L1 expression > 1% correlated with improved PFS, and variations in level of certain mRNA sequences were noted when comparing pts who had rapid disease progression vs. prolonged disease control with nivolumab. This suggests that BTC pts with positive PD-L1 expression and a particular mRNA profile may have a favorable response to nivolumab. Further studies are needed to confirm these findings. Clinical trial information: NCT02829918.
PALBI and ALBI score as a prognosis factor for liver metastasis undergoing transarterial radioembolization.
Authors: Sanchez-Garcia Jorge , Riegler Randie , Jepperson Maria , Gagnon Andrew , Alonso Diane , Fujita Shiro , Rodriguez-Davalos Manuel , Thota Ramya , Cannon George , Krong Jake , Dow Sean , Gilroy Richard , Kringlen Mark , Zendejas-Ruiz Ivan R
Published: January 2021

345

Background: Liver metastasis is evident in many oncological patients at the time of initial presentation. Recently, platelet-albumin-bilirubin (PALBI) score was reported to be superior to Child-Pugh classification and albumin-bilirubin (ALBI) score in terms of mortality prediction, while Model for End-Stage Liver Disease (MELD) score is the most frequent used. Trans-arterial radioembolization (TARE) is a minimally invasive therapy used to treat liver tumors. The aim of this study is to assess prognostic performance of pre-TARE liver function scores. Methods: We retrospectively assessed all patients with liver metastasis that underwent TARE between February 2008 and January 2020 at a single institution. Demographic characteristics; and laboratory values were collected to calculate MELD, ALBI, PALBI, within six months before TARE administration. Results are presented as proportions and median (IQR). Multivariate Cox regression analysis was performed to identify risk factors for overall survival. Results: A total of 90 patients were included, 46.7% were females with a median age was 61 (50-69). Colorectal (CR) metastasis was found in 45.6% of cases, neuroendocrine tumors (NET) in 27.8% and the remainder a heterogenous group of metastatic disease. In 90% of cases, TARE was used as destination therapy. The median tumor size was 5.1 (3.3-7.1) cm with 81% having multifocal lesions. The median scores were: MELD 8 (7-10), ALBI -2.77 (-3.01 to -2.56), PALBI -2.58 (-2.77 to -2.32). Other metastatic disease (OR=2.3: 95%CI 1.3-4.3; p=0.02), MELD (OR=1.1: 95%CI 1.002-1.2; p=0.04), ALBI (OR=2: 95%CI 1.2-3.3; p=0.005) and PALBI (OR=2.4: 95%CI 1.2-4.7; p=0.01) were significant in univariate Cox regression. In the multivariate Cox regression, MELD score was not statistically significant when adjusted with diagnosis and PALBI or ALBI score. As expected due to similar variables to calculate score, ALBI and PALBI score were not statistically significance when these are used in the same model (Table). Conclusions: To our knowledge, this is the first report of PALBI as prognostic factor in patients undergoing TARE for metastatic liver disease. Interestingly, the multivariate cox regression showed us that MELD score is not a significant score for these patients. Further non-inferiority assessment of PALBI and ALBI over MELD score should be developed. [Table: see text]