bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in prescribing patterns in stage III colon cancer (CC) since the IDEA collaboration.
Authors: Walden Daniel , Ou Fang-Shu , Larson Joseph J. , Wu Christina , Kang Sandra , Liu Alex John , Griswold Cassia R , Ueberroth Benjamin Edward , Patel Bhamini , Draper Amber , Rone Kelley , Raman Puneet , Bekaii-Saab Tanios S. , Ahn Daniel H. 
Published: January 2022

92 Background: Since the publication of the MOSAIC trial, stage III CC has been treated with a six-month (mo) regimen of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Recently, the IDEA collaboration challenged this practice by demonstrating that the 3-year rate of disease-free survival (DFS) was non-inferior to 6mo of treatment (Rx) when given for low risk CC (83.1 vs. 83.3%) and resulted in significantly lower rates of grade 2 and higher neuropathy. In high risk (T4, N2) patients (pts) the DFS of 3mo of CAPOX was equivocal to 6mo (64.1 vs. 64.0%), while 3mo of FOLFOX was inferior to 6mo (61.5 vs. 64.7%). We hypothesized that trends in prescribing would favor shorter courses of Rx with a preference towards CAPOX given its efficacy across both high and low risk CC. Methods: We performed a retrospective analysis of stage III CC pts from 4 institutions. We evaluated prescribing patterns of 3mo or 6mo of Rx and CAPOX vs. FOLFOX over a period of 5 years from Jan 2016 to Jan 2021, a time period that traverses before and after the release of IDEA. Logistic and multinomial logistic regression models, with a linear time trend, were used to estimate the percentage of pts receiving CAPOX vs. FOLFOX and the combination of Rx and duration, respectively, while adjusting for baseline characteristics. The prescribing patterns in important subgroups were examined by incorporating the interaction term in the models. Results: A total of 366 pts met inclusion criteria. From 2016-2021, there was a significant increase per quarter in patients treated with CAPOX when compared to FOLFOX (OR 1.16 95% CI 1.11 – 1.21, p <.001). Prior to IDEA, 78.3% of pts received 6mo FOLFOX and 7.4% received 3mo CAPOX. Two years after IDEA, only 17.3% of pts were on 6mo FOLFOX compared to 67.5% of pts on 3mo CAPOX (Table). At present, high risk pts are more likely to receive 6mo FOLFOX (47.8%) than 3mo of FOLFOX (3.9%), 3mo CAPOX (25.8%), or 6mo CAPOX (22.4%). Low risk pts are more likely to receive 3mo of CAPOX (67.9%) than other Rx. Conclusions: Our findings suggest that since IDEA, physician practice has significantly changed in favor of CAPOX and shorter courses of Rx. The use of CAPOX has significantly increased overall, presumably due to its efficacy across all risk groups and relatively reduced toxicity.[Table: see text]
AB1, a novel protein targeting TP53 mutated GI tumors.
Authors: Epenetos Agamemnon A. , Karagussova Karima , Deonarain Mahendra 
Published: January 2022

96 Background: The tumor suppressor gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. Normal p53 regulates several important proteins that control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. If the TP53 gene is damaged, tumor suppression is severely compromised. On the other hand, and downstream of p53, p21 a potent cyclin-dependent kinase inhibitor (CKI) protein binds and inhibitsthe activity of cyclin - CDK2, - CDK1, and - CDK4/6, thus functioning as a regulator ofcell cycle progression at G 1 and S phase. It can act as de facto p53 repair/ replacement mechanism. We have thus hypothesised that, if we were able to deliver wild type p21 into all p53 mutated cancer cells, it would have a possible therapeutic effect. Methods: We have constructed recombinantly a new fusion protein, named AB1, composed of a cell penetrating protein (antennapedia) ANTP and wild type p21 and tested it in in vitro and in vivo preclinical models prior to clinical studies. AB1 could also be constructed semi-synthetically by conjugating recombinant ANTP chemically to p21 protein. Results: AB1 penetrated and killed p53 mutated cancer cells but did not kill cells that did not have p53 mutations AB1 penetrated but did not kill p53- or p21- wild-type cells. AB1 was not immunogenic in normal New Zealand White rabbits. AB1 was more cytotoxic when administered with conventionally-used chemotherapeutic agents. Conclusions: We have generated a selectively cytotoxic fusion protein against p53 mutated GI cancers which is effective when used as a single agent but more so when used in combination with chemotherapy. The phaseI/II clinical trial will include eligible patients who have p53 mutated GI cancers
Ezabenlimab (BI 754091), an anti-PD-1 antibody, in combination with BI 836880, a VEGF/Ang2-blocking nanobody, in patients (pts) with advanced colorectal cancer (CRC).
Authors: Ulahannan Susanna Varkey , Percent Ivor John , Arrowsmith Edward , Hussein Maen A. , Bhanderi Viralkumar K. , Hamm John , Durm Greg Andrew , Erzen Damijan , Mohanty Prasant , Spigel David R. 
Published: January 2022

98 Background: Anti-PD-1 antibodies may have synergistic effects with other immunomodulatory or targeted agents. This open-label, Phase II platform trial is investigating ezabenlimab, an anti-PD-1 antibody, combined with other agents. Module C of the platform is assessing ezabenlimab plus BI 836880, a humanized bispecific nanobody targeting VEGF/Ang2. Pts are being enrolled into 5 advanced solid tumor cohorts: gastric/gastroesophageal adenocarcinoma; solid tumors (except non-squamous NSCLC or melanoma) with secondary resistance to anti-PD-(L)1 treatment (progression after at least SD for ≥4 months); solid tumors with primary resistance to anti-PD-(L)1 treatment; microsatellite stable (MSS) CRC; mismatch repair-proficient/MSS endometrial carcinoma. Here, we report data from the CRC cohort which has completed recruitment. Methods: Pts with locally advanced, unresectable or metastatic, MSS CRC were enrolled. Patients had received ≥1 line of prior systemic therapy for metastatic disease but were anti-PD-(L)-1 therapy-naïve. Prior anti-angiogenic therapy was permitted. Pts received BI 836880 720 mg plus ezabenlimab 240 mg iv q3w for 1 year or until disease progression, consent withdrawal or undue toxicity. Primary endpoint: investigator-assessed OR (CR or PR per RECIST v1.1). Secondary endpoints: duration of response, disease control, and PFS; safety is also being assessed. Results: 30 pts have been treated: 57% male; median age 61.5 years. All pts had received prior chemotherapy; most pts (23 [77%]) had received prior bevacizumab. At data cut-off (Sep 2021), median duration (range) of treatment was 115.5 (28–295) days; 6 pts remain on treatment. 1 (3%) pt (who had not received prior bevacizumab) achieved a confirmed PR; 16 (53%) pts had SD. Median duration (range) of SD was 128.5 (42–242) days. 29/17/2 (97/57/7%) pts had an AE (any/G3/G4). The most frequent AEs (any/G3) were nausea (40/10%), fatigue (30/3%), peripheral edema (30/0%), vomiting (27/7%), and hypertension (27/17%). There were two G4 AEs (hypertension; platelet count decreased) and no G5 AEs. 24/10/2 (80/33/7%) pts had a drug-related AE (any/G3/G4); most commonly (any/G3) nausea (33/7%), fatigue (27/3%) and hypertension (27/17%). 3 (10%) pts had an infusion-related reaction (G1, n = 1; G2, n = 2). 2 (7%) pts had an AE leading to discontinuation (G3 bile duct stone and G2 peripheral edema). Immune-related AEs were reported in 6 (20%) pts and serious AEs occurred in 13 (43%) pts. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile in pts with advanced MSS CRC; however, anti-tumor activity was limited in these pts, the majority of whom had received prior bevacizumab. Clinical trial information: NCT03697304.
QoL analysis: A randomized phase 3 study of sequential versus combination treatment in first-line chemotherapy for metastatic colorectal cancer—The C-cubed study.
Authors: Noura Shingo , Inada Ryo , Ojima Hitoshi , Nagasaka Takeshi , Tanioka Hiroaki , Munemoto Yoshinori , Shimada Yasuhiro , Ishibashi Keiichiro , Shindo Yoshiaki , Shimokawa Mototsugu , Mishima Hideyuki , Yamaguchi Yoshiyuki , Okajima Masazumi ,   The C-cubed study group
Published: January 2022

102 Background: The C-cubed (C3) study demonstrated a sequential approach start from ﬂuoropyrimidines (FP) plus bevacizumab (Bmab) followed by oxaliplatin (OX) adding significantly improved a median Treatment failure of strategy (TFS) for a combination approach start from FP+OX+Bmab [15.2 months vs. 7.6 months, HR, 0.475; 95% CI, 0.362 to 0.623; p < 0.0001] in first-line metastatic colorectal cancer (mCRC). In this congress, we focus on the quality of life (QOL) assessments as a pre-planned analysis. (Study information: UMIN000015405). Methods: The C3 study was a randomized phase III study which evaluated the time to discontinuation of OX-containing therapy (sequential approach [Capecitabine/5-FU (FP)+Bmab followed by OX-FP+Bmab] vs. combination approach [OX-FP+Bmab]. The primary endpoint was TFS and secondary endpoints were ORR, OS, PFS, Safety and QoL. QOL assessments included European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) (EORTC QLQ C-30), EuroQol 5D 5L (EQ5D) and the Patient Neurotoxicity Questionnaire (PNQ) in both arm as a pre-planned analysis. Each questionnaire was collected at the time of enrolment, 6, 12, 18 months and end of treatment. QOL scores were compared using a mixed-effects models for repeated measures (MMRM). Results: A total 292 patients participated in QoL part (arm A: n =148; arm B: n =144). The returned questionnaire sheets were 292 (reply rate: 97%), 206 (68%), 199 (65%), 61 (20%) at baseline, 6, 12, 18 months, respectively. Sequential approach was statistically improved than combination approach as follows: Physical functioning (p<0.001), Cognitive functioning (p=0.012), Social functioning (p=0.0004), and Fatigue (p=0.013) in EORTC QLQ C-30. In addition, at 6 months (after which attrition in the combination arm was more than 50%) after randomization, the mean change rate from baseline of EQ5D score in the sequential approach versus combination approach were: –1.91 (SD 27.57) versus –9.62 (29.60). In contract, PNQ sensory score showed that sequential approach was not statistically improved for combination approach (0.22 [SD: 0.89] vs. 0.61 [SD: 0.95], p=0.115). Conclusions: The further clarification of patients’ characteristics are needed, but this sequential approach can be advocated as a valuable treatment option in first-line mCRC for current guideline based on these QoLs and main efficacy data.
Evaluating the technical feasibility of novel salvage endoscopic submucosal dissection after chemoradiotherapy for locally advanced rectal adenocarcinoma.
Authors: Leung Galen , Nishimura Makoto , Hingorani Neha , Lin I-Hsin , Schattner Mark 
Published: January 2022

103 Background: According to the National Comprehensive Cancer Network guideline, locally advanced rectal cancer is treated with chemotherapy with or without radiation, followed by transabdominal resection. However, there has been an emerging role for nonoperative management after chemoradiotherapy, and there is significant morbidity and risks associated with surgical resection. Endoscopic submucosal dissection (ESD) after chemoradiotherapy (CRT) for rectal cancer, which is termed “salvage ESD,” may be a viable option for patients, in terms of evaluating pathological response and providing potential curative resection. We aim to evaluate the feasibility and safety of salvage ESD. Methods: Retrospective chart review of cases of salvage ESD after CRT for locally advanced rectal cancer (salvage group) and standard ESD cases for rectal tumors without prior CRT (standard group) from July 2018 to August 2020 at our institution was performed. Clinical factors, imaging, procedural, and pathology results were collected and compared between the two groups. Results: 12 salvage ESD cases were compared to 27 standard ESD cases. 83.3% of the lesions in the salvage ESD group were initially staged as T3 prior to CRT. 100% of the lesions in the salvage ESD group were scarred down, compared to 33.3% in the standard ESD group (p <0.01). Technical outcomes are shown in the table. The en bloc resection rates were 92.7% and 91.7% (p=1.00) and R0 resection rates were 66.7% and 75.0% (p=0.55) for the standard and salvage groups, respectively. In the salvage ESD group, no adverse events were observed. 66.7% of the adenocarcinomas in the salvage ESD group had morphologically changed to hyperplasia or adenoma after CRT and there were no identifiable lesions greater than T1 staging. Conclusions: Salvage ESD after CRT for locally advanced rectal cancer is technically feasible and with comparable low complication rates. There may be a diagnostic role in salvage ESD in assessing pathological response to CRT, as well as a possibly therapeutic role in resection of residual lesions with the potential to avoid surgery. Further studies are underway comparing the clinical outcomes of salvage ESD with standard surgical resection after CRT for locally advanced rectal cancer.[Table: see text]
Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC: A single-arm, multicenter, phase II clinical trial—Update results from ALTER-C001.
Authors: Yan Jin , Han Yunwei , Zhang Li , Jin Yongdong , Sun Hao 
Published: January 2022

104 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial (NCT02332499). We present updated data from the study of anlotinib plus XELOX as first-line treatment followed by anlotinib monotherapy for mCRC. Methods: In this open label, single-arm, multicenter phase II clinical trial, 29 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: At updated analysis (cutoff: Sep 10, 2021), a total of 27 patients were enrolled, of which 19 patients were available for efficacy assessment. In best overall response assessment, there were 63.2% PR (12/19), 26.3% SD (5/19) and 10.5% PD (2/19). The ORR was 63.2% (95% CI, 38.4-83.7%) and DCR was 89.5% (95% CI, 66.9-98.7%). One patient experienced the longest duration of treatment which was 17.5 months. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥25%) were leukopenia, nausea/vomiting, hypertension, neutropenia, hypohemoglobinemia, hypertriglyceridemia. Grade 3/4 TRAEs (≥10%) were neutropenia (14.8%), hypertension (14.8%) and hypertriglyceridemia (11.1%). One grade 5 TRAE was pancytopenia that occurred at 2.7 months. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed promising anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in randomized studies. Clinical trial information: ChiCTR1900028417.
A phase II study of pembrolizumab, binimetinib, and bevacizumab in patients with microsatellite-stable, refractory, metastatic colorectal cancer (mCRC).
Authors: Friedrich Tyler , Blatchford Patrick Jud , Lentz Robert William , Davis S. Lindsey , Kim Sunnie S. , Leal Alexis Diane , Van De Voorde Zoe , Lee Matthew R , Waring Meredith , Cull Tiffany , Martin Anne , Eckhardt S. Gail , Messersmith Wells A. , Lieu Christopher Hanyoung 
Published: January 2022

118 Background: To date, immune-checkpoint inhibition for microsatellite stable (MSS) mCRC has been ineffective, though targeted therapy combination strategies may be promising. This phase II, investigator-initiated trial (NCT03475004) was designed to evaluate the efficacy and safety of the three-drug combination of pembrolizumab (pembro), binimetinib, and bevacizumab in patients with advanced, MSS treatment-refractory colorectal cancer. Methods: Patients with mCRC locally determined to be MSS and whom have progressed on two prior lines of therapy were enrolled. Treatment consists of pembro (200 mg every 3 weeks), binimetinib (45 mg BID) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint is PFS using RECIST v1.1 by investigator review. Additional endpoints include objective response rate, disease control rate at time of first re-staging (2 mo), duration of response, and safety and tolerability. Results: 50 patients have been enrolled (accrual is completed). 53% of patients are male and the mean age is 53.6 (range 31-79). The mean number of prior therapies is 5.3. At the time of preliminary data review, 39 patients are evaluable for response data. The median PFS was 5.8 mo (95% CI 4.2 to 8.9). The objective response rate was 13% with 5 partial responses. 24 patients (62%) had stable disease and 10 (26%) had progressive disease as the best response. The disease control rate at the time of first re-staging was 74%. Median duration of response was 6.5 mo. 19 (40%) patients experienced serious adverse events; the most common grade ≥3 adverse events included transaminase elevation (15%), diarrhea (11%), acneiform rash (9%), hypertension (9%), and anemia (9%). Conclusions: Preliminary results from this phase II study indicate that this regimen of pembrolizumab, binimetinib, and bevacizumab has promising activity and acceptable tolerability in this heavily pre-treated population of patients with MSS metastatic colorectal cancer. Final results will be presented as well as ongoing correlative studies. Clinical trial information: NCT03475004.
Tumor volume regression of rectal cancer in daily MRI during preoperative chemoradiotherapy with capecitabine.
Authors: Kwak Yoo-Kang , Lee Sea-Won , Jung Yoon Ju 
Published: January 2022

123 Background: Although cone beam computed tomography (CBCT) has been available for over a decade, the pattern of tumor volume change in rectal dancer during preoperative concurrent chemoradiotherapy (CCRT) has been under the veil due to poor soft tissue contrast of registration CBCT. This study was conducted to investigate daily rectal tumor volume change using registration magnetic resonance imaging (MRI). Methods: Patients diagnosed with cT3-4 and/or cN+ rectal adenocarcinoma undergoing preoperative CCRT with capecitabine on the pelvis up to 50 Gy in 25 daily fractions from November 2018 to June 2019 were consecutively included. Rectal tumor volume was uniformly measured by single physician (YKK) in daily 0.35T MRI obtained with ViewRay MRIdian Linac (ViewRay Inc., Oakwood, USA). The mean +/- standard deviation (SD) of daily tumor volume (cc), difference of tumor volume between first fraction and daily fraction (daily tumor volume – baseline tumor volume at first fraction), and tumor volume reduction rate (%, (daily tumor volume – baseline tumor volume at first fraction)/baseline tumor volume at first fraction x 100) were calculated. Statistical significance of differences were tested using the Wilcoxon’s signed rank test and paired t-test. Results: Thirteen patients were included. Median age was 65 and majority of the patients were male (92.3%). Most tumors were T3 (76.9%) and N1-2 (92.3%). Tumors were located median 6 cm (range: 2.4 – 9) above anal verge. Median follow-up was 27.3 months (range: 11.7 – 30.6) and 2 patients had recurred at the time of analysis (1 local and 1 distant). Tumor volume steadily regressed with daily administration of CCRT (mean 2.06 +/-1.73 cc; Figure 1). Significant tumor volume reduction compared to baseline was observed from fourth fraction (mean -12.37 +/- 16.72 cc; P < 0.0005). The difference of tumor volume between baseline and the last fraction was mean -49.33 +/- 68.13 cc ( P < 0.0002). The tumor volume reduction rate was significantly increased since fourth fraction (mean - 17.2 +/- 11.78 %; P < 0.0002). The tumor volume reduction rate at the last fraction was - 70.62 +/- 14.01 % ( P < 0.0001). Conclusions: For the first time, this study demonstrated daily tumor volume regression in preoperative rectal CCRT with capecitabine using daily MRI. Steady pattern of tumor regression may be explained in part by daily administration of capecitabine. Based on the hypothesis-generating observation, this study may warrant initiation of further investigations such as analysis and comparison with daily tumor volume regression with CCRT using leucovorin and 5-FU.