bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency and distribution of gastrointestinal oncology patient-reported symptomatic adverse events (SAEs) at a comprehensive cancer center.
Authors: McCleary Nadine Jackson , Haakenstad Ellana , Cleveland Jessica , Zhang Sunyi , Hassett Michael J. , Schrag Deborah 
Published: January 2021

463 Background: In clinical trials, the systematic collection of patient (pt) reported outcomes has been shown to improve quality of life & overall survival. To develop predictive care models for symptom management, we explored the frequency & distribution of SAEs reported by pts who reported electronic patient reported outcomes (ePRO) prior to outpatient visits to the Gastrointestinal Cancer Center (GCC) at Dana Farber Cancer Institute (DFCI). Methods: ePRO is a modified NCI Patient Reported Outcomes – Common Terminology Criteria for Adverse Events instrument distributed weekly to GCC pts with a medical/surgical/radiation oncology encounter. Responses are available to the care team in the electronic health record. ePRO consists of presence/frequency/severity/interference of 15 core SAEs (fatigue, insomnia, general pain, decreased appetite, nausea, vomiting, constipation, diarrhea, shortness of breath, numbness and tingling, rash, concentration, fever, anxiety, sadness). Responses are scored 0 to 3 (with 2 and 3 indicating moderate and severe SAEs, respectively). We examined the frequency & distribution of grade 2 and 3 SAEs in ePRO responders by age, gender, race/ethnicity. All pts had gastrointestinal cancer and an outpatient visit for treatment, symptom management, follow-up care. Results: From 9/1/2018 to 8/31/2020, 1912 unique pts responded (response rate 23%). Most respondents were age 50-69 years (58% compared to 15% age <50, 27% age ≥70; range 18-95), male (53%), white (75%). Grade 3 SAE frequencies were pain (12%), fatigue (11%), anxiety/constipation/insomnia/decreased appetite (5%), sadness/numbness and tingling/diarrhea (3%), concentration/shortness of breath (2%), nausea/rash (1%), fever/vomiting (0%). Across pts, fatigue, general pain, insomnia, anxiety were the most common grade 2 and 3 SAEs. Shortness of breath, vomiting, rash, fever were least common (Table). Conclusions: In GCC pts responding to ePRO, the most frequent SAEs were pain, fatigue, insomnia, anxiety. Shortness of breath, nausea, vomiting, diarrhea were less often severe. Pts <50 were more likely to report severe anxiety but there were no other major differences based on age, sex, race/ethnicity. Ongoing efforts will increase pt/provider engagement and develop predictive models & symptom management interventions from ePRO responses. [Table: see text]
Targeting GNAS mutant appendiceal adenocarcinoma.
Authors: Haridas Valsala , Ito Ichiaki , Shen John Paul Y.C. 
Published: January 2021

470 Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, preventing the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease and no drugs have been developed to specifically target appendiceal adenocarcinoma (AA). The G protein GNAS is the second most frequently mutated gene after KRAS in low-grade (49%) mucinous AA (52%), making it an attractive drug target in this orphan disease. Methods: Using CRISPR, GNAS was knocked out in KM12, SNU175 and SKCO1 gastric cell lines that harbor GNASR201C mutation. The mutant and KO pairs of cells were evaluated for their proliferation rate and ability to form colonies in a clonogenic assay. RNA sequencing of the mutant and knock out cells was performed to determine pathways potentially associated with the GNAS signaling pathway. The Sanger GDSC was used to identify drugs selectively lethal to GNAS mutant tumors. Results: KM12 cells knocked out for GNAS showed a 40% decrease in proliferation compared to the parent cells with mutant GNAS (p < 0.0001). GNAS knockout significantly reduced colony formation of all three mutant cell lines (KM12: 397 vs. 94, SNU175: 512 vs. 134, and SKCO1: 36 vs. 5, p = 0.0022). Analysis of four GNASR201C cell lines relative to matched controls identified IGF-1R, MEK and PKC as potential vulnerabilities. In vivo validation experiments are currently ongoing. Conclusions: Our findings suggest preliminarily that GNASR201C mutant cell lines are oncogene addicted to GNAS growth signal and could be targeted with inhibitor of GNAS or one of its downstream effectors.
Effect of food on exposure to napabucasin: Data from two phase I studies.
Authors: Dai Xiaoshu , Noda Naoto , Xie Yuran , Xu Bo , Hitron Matthew , Karol Michael 
Published: January 2021

477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]
Evaluating adherence to post-treatment follow-up of colorectal cancer at a reference center in Mexico: A retrospective analysis.
Authors: Hernandez-Felix Jorge Humberto , Meneses Medina Mónica Isabel , Rivera Aguilar Mauricio , Valenzuela Ana Karen , Camargo Vanessa Rosas Rosas , Cedro-Tanda Alberto , Huitzil Melendez Fidel David 
Published: January 2021

51 Background: Adequate post-treatment surveillance for colorectal cancer (CRC) is recommended by all major societies with the intention to improve overall survival. However, compliance is variable and has not been studied in our country. Our aim was to evaluate the adherence to post-treatment surveillance NCCN guidelines for CRC at our Institution in Mexico City. Methods: We retrospectively reviewed charts from patients with stage I-III CRC who were diagnosed between January 2014 and December 2016. Adherence to surveillance was evaluated for the first 3 years after completion of oncologic treatment or until recurrence, whichever came first. We used an adherence composite definition previously defined by Cooper et al, where adequate compliance with guidelines was considered if patients had ≥2 physician visits per year for 3 years, ≥2 CEA tests per year for 2 years, and at least one colonoscopy in the 3-years surveillance period. Results: We included 90 patients. Mean age at diagnosis was 62 ± 12.5 years, 53% (n=48) were male, 68% (n=62) had colon cancer and 31% (n=28) rectal cancer. According to AJCC7 19% (n=17) were Stage I, 39% (n=35) II, and 42%(n=38) III. Median score for Charslon index at diagnosis was 4 (IQR 3-6). Results of follow-up adherence are presented in Table. Just 12% (n=11) of patients had a PET/CT or any other non-indicated imaging study for surveillance. Recurrence rate at the 3rd year of surveillance was 6.6% (n=6). A bivariate analysis was performed to find clinical and demographic factors associated to adherence and individual components of surveillance, we did not find any significative association. Conclusions: At our institution compliance with follow-up guidelines for CRC is good and higher than reported by other centers, though individual components have a decreasing trend in adherence every year. This could be explained because in our Institution cancer surveillance is performed by a medical oncologist. The main limitation of our study is that it involves an individual reference center in Mexico; thus, extrapolating data may not be feasible. [Table: see text]
Change in skeletal muscle index and its prognostic significance in conversion therapy for initially unresectable colorectal cancer.
Authors: Nozawa Hiroaki , Emoto Shigenobu , Murono Koji , Shuno Yasutaka , Ishihara Soichiro 
Published: January 2021

56 Background: Systemic chemotherapy can cause loss of skeletal muscle mass in colorectal cancer (CRC) patients in the neoadjuvant and palliative settings. However, it is largely unknown how the body composition is changed by chemotherapy rendering unresectable CRC to resectable disease or how it affects the prognosis. This study aimed at elucidating the effects of systemic chemotherapy on skeletal muscles and survival in stage IV CRC patients who underwent conversion therapy. Methods: We reviewed 98 stage IV CRC patients who received systemic chemotherapy in our hospital. According to the treatment setting, patients were divided into the ‘Conversion’, ‘Neoadjuvant chemotherapy (NAC)’, and ‘Palliation’ groups. The cross-sectional area of skeletal muscles at the third lumbar level and changes in the skeletal muscle index (SMI), defined as the area divided by height squared, during chemotherapy were compared among patient groups. The effects of these parameters on prognosis were analyzed in the Conversion group. Results: The mean SMI increased by 8.0% during chemotherapy in the Conversion group (n = 38), whereas it decreased by 6.2% in the NAC group (n = 18) and 3.7% in the Palliation group (n = 42, p < 0.0001). Moreover, patients with increased SMI during chemotherapy had a better overall survival (OS) than those whose SMI decreased in the Conversion group (p = 0.021). The increase in SMI was an independent predictor of favorable OS on multivariate analysis (hazard ratio: 0.26). Conclusions: Stage IV CRC patients who underwent conversion to resection often had an increased SMI. As such an increase in SMI further conveys a survival benefit in conversion therapy, it may be important to make efforts to preserve muscle mass by meticulous approaches, such as nutritional support, muscle exercise programs, and pharmacological intervention even during chemotherapy in patients with metastatic CRC.
Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.
Authors: Bando Hideaki , Kotani Daisuke , Kotaka Masahito , Kawazoe Akihito , Masuishi Toshiki , Satake Hironaga , Taniguchi Hiroya , Yamazaki Kentaro , Yamanaka Takeharu , Oki Eiji , Yoshino Takayuki , Muro Kei , Komatsu Yoshito , Kato Takeshi , Tsuji Akihito 
Published: January 2021

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.
Anlotinib combined with CAPEOX in first-line treatment of patients with RAS and BRAF wild-type unresectable metastatic colorectal cancer: A single-arm, phase II study (ALTER-C-002 trial).
Authors: Ding Ke-Feng , Liu Yue , Chen Jiaqi , Sun Lifeng , Xu Dong , Liao Xiujun , Xiao Qian , LI JUN , Yuan Ying 
Published: January 2021

75 Background: Anlotinib is an oral small molecule multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR1/2/3, FGFR1-4, PDGFR α/β and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. In a previous trial, Anlotinib had been demonstrated to be safe and efficacious in advanced colorectal cancer after failure of recommended treatment. We aimed to evaluate the efficacy and safety of Anlotinib combined with CAPEOX as first-line treatment for unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC). Methods: ALTER-C-002 is a single-arm phase II clinical trial. A total of 30 patients with RAS/BRAF wild-type unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance score ≤ 1 will be prospectively included. Patients received Capecitabine (850 mg/m2, p.o., on day 1-14 every 3 weeks), Oxaliplatin (130 mg/m2, i.v., every 3 weeks) and Anlotinib (12 mg, p.o., 2 weeks on/1 week off). After 6 cycles of inducing therapy, patients will receive Capecitabine and Anlotinib as maintenance therapy until tumor progression. Primary endpoint was objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: As of Sep.15th, 2020, 19 patients had been enrolled. 12 of 19 patients were evaluable for antitumor activity: 10 patients had partial response, 2 patients had stable disease. The ORR was 83.3% (95% CI: 51.6–97.9%), and DCR was 100% (95% CI: 73.5–108.1%). 9 patients (47.4%) developed grade Ⅲ adverse events with 1 (5.3%) grade Ⅳ AE. The grade Ⅲ AEs included hypertension (n = 8), diarrhea (n = 3), hypertriglyceridemia (n = 2), leukopenia and neutropenia (n = 3), alanine aminotransferase increase (n = 1), intestinal obstruction (n = 1), nausea and vomiting (n = 1), and grade Ⅳ AE was blood bilirubin increase. 1 patient received emergent surgery for relieving intestinal obstruction after 14 days of Anlotinib treatment discontinuation. No extra bleeding or wound healing risk were observed during the perioperative period. No treatment-related deaths occurred. Conclusions: The combination of Anlotinib and CAPEOX displayed promising antitumor activity and manageable toxicity in unresectable RAS and BRAF wild-type mCRC, which should be merited further evaluation in randomized studies. Clinical trial information: NCT04080843.
NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—Pembrolizumab experimental arm (EA) primary results.
Authors: Rahma Osama E. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Colangelo Linda H. , Lucas Peter C. , Gollub Marc J , Hall William Adrian , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman , George Thomas J. 
Published: January 2021

8 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk pt population with correlative biomarkers. Here we report the primary and available secondary endpoints (EPs). Methods: Stage II/III LARC pts (with ONE or more of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy +/- pembrolizumab 200mg IV Q3 wks x 6 doses) → surgery 8-12 wks following last dose of radiotherapy. Primary EP: Improvement in Neoadjuvant Rectal Cancer (NAR) score for EA v control potentially representing a 3-4% absolute OS improvement. Secondary EPs: Comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter sparing surgery (SSS), and exploratory assessments of molecular and radiographic predictors of response and distant failure. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 8/2018-5/2019, 185 pts were randomized to control (n=95) or pembrolizumab (n= 90). Baseline characteristics were relatively well balanced. 137 pts were evaluable for NAR (68 control, 69 pembrolizumab). Mean NAR was 14.08 for control (95% CI: 10.7-17.4) v 11.53 for pembrolizumab (CI: 8.5-14.6) (p=0.26). pCR=29.4% v 31.9% (p=0.75); cCR=13.6% v 13.9% (p=0.95); and SSS=71.0% v 59.4% (p=0.15). The side effects on Arm 3 were consistent with both CRT and pembrolizumab safety profile. Grade 3/4 AEs were slightly increased on the pembrolizumab arm during and after CRT (48.2 v 37.3%). There were 2 deaths during FOLFOX, one on the control arm due to sepsis; the other on the EA due to pneumonia. There were no statistically significant differences in RT (fractions, dose, boost fractions, or boost dose), FOLFOX or capecitabine doses. Conclusions: Pembrolizumab added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. The secondary endpoints including PFS and OS have not been reached. Correlative analysis for both T-cell and myeloid cell populations in the tissue and blood in addition to comprehensive cytokine analysis is ongoing. NCT02921256. Support: U10CA180868, -180822; UG1-189867; U24-196067. Clinical trial information: NCT02921256.
Is antiangiogenic therapy necessary for patients with metastatic colorectal cancer (mCRC) and mutation in the BRAF gene? Results of the systematic review and meta-analysis.
Authors: Fedyanin Mikhail , Polyanskaya Elizaveta , Elsnukaeva Kheda , Tryakin Alexey , Pokataev Ilya , Tjulandin Sergei 
Published: January 2021

88 Background: There are no direct prospective randomized studies supporting the need for antiangiogenic drugs in the treatment of patients with the m BRAF mCRC. However, subgroup analysis of different studies showed conflicting results. Therefore, we performed systemic review and meta-analysis to compare efficacy anti-angiogenic targeted therapy with chemotherapy and chemotherapy alone in patients with m BRAF mCRC in terms of progression free survival (PFS), and overall survival (OS). Methods: We performed a search of all prospective randomized phase III studies in PubMed, ASCO and ESMO congresses for all years before September, 2020, compared chemotherapy (CT) plus bevacizumab or aflibercept or ramucirumab and CT alone at the first-line or second-lines with information of the BRAF status. Primary outcome was hazard ratio (HR) for PFS and 95% confidence interval (CI); secondary–HR for OS and 95%CI. Fixed effects were used for analysis. Meta-analysis was conducted by "Review Manager" Ver. 5.3. Results: We identified 4 trials (AVF2107g, AGITG MAX, VELOUR and RAISE), which included 120 patients with mBRAF (anti-angiogenic plus CT–65 (54%) and CT alone–55 (46%). According to results of the meta-analysis there was a tendency for significant improvement in PFS (HR 0.64, 95% CI 0.4-1.02; p = 0.06; I2 = 0%, p for heterogeneity 0.7; 53trials) and significant improvement in OS (HR 0.51, 95% CI 0.32-0.82; p = 0.005; I2 = 0%, p for heterogeneity 0.52; 4 trials) in group of ani-angiogenic therapy. Conclusions: Addition of anti-angiogenic therapy to chemotherapy showed improvement in the PFS and OS in pts with m BRAF compared with chemotherapy alone. A prospective randomized trial is needed to determine the optimal regimen of systemic therapy for pts with m BRAF mCRC.