bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil monotherapy for refractory metastatic colorectal cancer: A retrospective study.
Authors: Li Rongrong , Zhou Hui-Jun , Zeng De-Yu , Jiang Shao-Feng , Liu Wu , Liu Zhen-yang 
Published: June 2023

e15562 Background: There had been no phase III trial to compare the efficacy between trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) with TAS-102 monotherapy in refractory metastatic colorectal cancer (mCRC). Our study sought to investigate the efficacy and safety of TAS-102 plus BEV versus TAS-102 monotherapy in these patients. Methods: We retrospectively analyzed the patients with refractory mCRC who received TAS-102 (35 mg/m2 twice daily; day 1–5 and 8–12; every 28 days) with or without BEV (5 mg/kg; day 1,15; every 28 days) between November 2020 and October 2022 in Hunan Cancer Hospital. All patients had previously received at least second-line treatment. The primary endpoint was overall survival (OS). Results: A total of 58 patients received TAS-102 plus BEV, and another 32 patients received TAS-102 monotherapy. With a median follow-up of 4.60 months (range, 0.20–22.80), the median overall survival (mOS) was 10.83 months [95% confidence interval (CI), 10.10–NA] for TAS-102 plus BEV, 7.43months (95% CI, 5.17–NA) for TAS-102 monotherapy. The hazard ratio (HR) was 0.90 (95% CI, 0.42–1.92), P= 0.78. Median progression-free survival (mPFS) was 4.67 months (95% CI, 3.57–7.37) for TAS-102 plus BEV, and 4.30 months (95% CI, 3.03–NA) for TAS-102 monotherapy. The HR was 1.04 (95% CI, 0.54–1.99), P= 0.91. The Cox multivariate regression analysis demonstrated that the patients who received treatment after TAS-102 with or without BEV(HR:0.25;95% CI, 0.09-0.71) and previously undergone Irinotecan (HR:0.23;95% CI, 0.06-0.95) were independent risk factors for OS and the patients who previously received Cetuximab was confirmed to have a significant better PFS(HR:0.17;95% CI, 0.03-0.91). Of the 70 patients who were evaluated, the TAS-102 plus BEV showed higher ORR and DCR than TAS-102 monotherapy, but the difference was not significant (ORR: 12.2% versus 0%; p= 0.16; and DCR: 77.5% versus 61.9%; p= 0.29). The incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group than the TAS-102 monotherapy group (3.00% vs. 0.00%, p = 0.03), whereas other adverse events were comparable between the two groups. Conclusions: Compared with TAS-102 monotherapy, TAS-102 plus BEV seemed to have comparable safety but improved disease control and prognosis in patients with refractory mCRC, although the difference was not significant. Further prospective studies are still needed to confirm our conclusions. [Table: see text]
Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.
Authors: Fumet Jean-David , Bertaut Aurelie , Roussot Nicolas , Bellio Hélène , Bengrine-Lefevre Leila , Vincent Julie , Niogret Julie , Palmier Rémi , Collot Thomas , Rambach Laurie , Boudrant Axelle , Parnalland Sophie , Rederstorff Emilie , Hennequin Audrey , Zanetta Sylvie , Hervieu Alice , Ghiringhelli François 
Published: June 2023

e15563 Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients > 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .
Clinical and molecular characterization of HER2-low metastatic colorectal cancer.
Authors: Babkoff Aryeh , Keidar Haran Tal , Zick Aviad , Hubert Ayala , Grinshpun Albert 
Published: June 2023

e15573 Background: HER2 is a well-established biomarker and target in multiple tumor types, including metastatic colorectal cancer (mCRC). Despite the lack of HER2 amplification, certain HER2-low tumors were recently found to respond to novel HER2-directed antibody-drug conjugates, warranting an exploration of the clinical and molecular features of these entities. Yet, the real-world prevalence and the clinicopathologic characteristics of HER2-low mCRC are largely unknown. Here, we aim to describe the features of HER2-low mCRC and compare them to HER2-0 colorectal tumors. Methods: We retrospectively reviewed clinicopathologic data from consecutive patients with mCRC undergoing HER2 testing (immunohistochemistry [IHC] and in-situ hybridization [ISH], when appropriate) between 2017 and 2021 at Hadassah Medical Center, Israel. Tumors were defined HER2-positive (HER2+) if scored IHC 3 + or IHC 2+/ISH positive; HER2-low if scored IHC 2+/ISH negative or IHC 1+; HER2-0 if scored IHC 0. Genomic alterations were determined through a targeted next-generation sequencing (NGS) panel. Clinicopathologic and genomic data were compared between the cohorts with the Mann-Whitney or Fisher's exact test, and survival using Log-rank test. Results: A total of 100 consecutive mCRC patients were found eligible for our study, including 4 (4%) with HER2+, 30 (30%) with HER2-low, and 66 (66%) with HER2-0 disease. In the HER2-low group, five tumors were HER2 +2 / ISH negative, and 25 were scored HER2 +1. The fraction of female patients was 40% in HER2-low group, and 42% in the HER2-0 cohort (p > 0.99). The prevalence of mismatch repair deficient (MMR-D) tumors was also similar, with one MMR-D tumor in the HER2-low group, compared to 3 tumors in the HER2-0 (p > 0.99). 60% of the primary tumors in both groups originated in the left colon and rectum. Also, the prevalence of mucinous histology was comparable between the HER2-low and the HER2-neg cohorts (7.4% vs. 4.8%, p = 0.64). Among patients receiving local somatic NGS testing (n = 61), the fractions of patients with KRAS, BRAF, and TP53 mutations were largely comparable between the cohorts (Table 1). With a median follow up of 37 months, the median overall survival was 41 months for the HER2-low group and 51 months for the HER2-neg group (p = 0.15). Conclusions: In our cohort of patients with HER2-negative mCRC, the clinicopathologic and genomic characteristics of HER2-low and HER2-0 tumors did not differ significantly. However, our data suggest that HER2-low tumors represent a significant portion of mCRC, supporting further development of novel HER2-directed therapies for this population. Additionally, our data also support the notion that HER2-low, as currently defined, is not a distinct molecular subtype of mCRC. [Table: see text]
Refractory colorectal cancer patient derived MicroOrganoSpheres (MOS) to enable correlation of targeted therapy combination response with clinical outcomes.
Authors: Ding Shengli , Kanikarla Marie Preeti , Baro Nicholas , Raman Renuka , Helman Elena , Hsu Shiaowen David , Kopetz Scott , Shen Xiling 
Published: June 2023

e15574 Background: Metastatic colorectal cancer (CRC) patients who have become resistant to standard-of-care (SOC) treatments are often put on targeted therapies, including experimental drugs still in clinical trials. However, patients with targeted mutations still often do not respond to the targeted therapies alone, hence it remains a critically unmet need to explore potential combinatorial regimens that will enhance the efficacy. Methods: We performed a high-throughput screen using MicroOrganoSpheres (MOS) derived from metastatic refractory patients to correlate with clinical outcomes and explore alternative combinations that might benefit the patients. Biopsies from metastatic CRC patients who became resistant to SOC and were about to receive targeted therapies in clinical trials were molecularly profiled and implanted into immunodeficient mice to generate patient-derived xenografts (PDX). Results: MOS were derived and established from PDX using droplet-based microfluidics for high-throughput 3D screening. These MOS-based refractory patient avatars contain either targetable mutations including KRAS G12C and BRAF 600E or no such mutations. Response of the MOS to dose-titrated single and combination drug treatments including the available targeted therapies were measured by a fully automated robotic dispensing and imaging pipeline and quantified by AI-based live imaging analytical algorithm to generate robust drug response curves, which were used to derive IC50 and EC50. We tested both FDA-approved and experimental targeted therapies as single agent or in combination in 5-dose titrations. Longitudinal tracking of each MOS with Live/dead fluorescence dye signals was obtained for 5 days. MOS drug response curves and IC50s show correlation with clinical outcomes. This comprehensive dataset enabled us to assess the potential benefit of different combinations, help deconvolute the efficacy and synergy of individual drugs, and provide insight into patients who fail to response to targeted therapies despite possessing the targeted mutations. As the MOS diagnostic assay can be completed from a patient biopsy within 10 days and is currently in a registered, multi-site clinical trial (ClinicalTrials.gov # NCT05189171), this study provides proof-of-principle for a potential clinical MOS-based assay to guide refractory patients to the optimal combination regimen containing targeted therapy. Conclusions: Refractory patients may benefit from a MOS-based high-throughput screen assay to select the optimal combination regimen containing targeted therapy.
The preventive effect of celecoxib on regorafenib-associated hand-foot syndrome in patients with liver metastasis from colorectal cancer: A single-center, retrospective, real-world study.
Authors: Wang Lijun , Wang Hongwei , Liu Wei , Jin Kemin , Bao Quan , Wang Kun , Xing Baocai 
Published: June 2023

e15576 Background: Regorafenib, an oral multi-kinase inhibitor, is the third- or later-line therapy for colorectal cancer with liver metastasis (CRLM), but the hand-foot syndrome (HFS) is its most common adverse reaction. Celecoxib, a selective COX-2 inhibitor, can treat inflammation. This study aimed to explore whether additing celecoxib to the cancer therapy regorafenib can prevent or alleviate the HFS, improve drug tolerance, and prolong the patient’s survival. Methods: In the retrospective cohort analysis, patients with colorectal cancer and liver metastasis, to whom regorafenib and celecoxib were administered in the Department of Hepatopancreatobiliary Surgery of Beijing Cancer Hospital between November 2021 and October 2022, were included. Upon the medical records from physical examination and other means of follow-ups, the Kaplan-Meier estimator analyzed the survival function and the severity of adverse events was described according to the CTCAE v.5.0 standards. Results: Twenty-six patients were included in the analysis and 14 colorectal cancer patients had extrahepatic metastases at the onset of the treatment. All patients received regorafenib and celecoxib. Further, 15 patients were treated with a combination of immune checkpoint inhibitors, 3 patients underwent combined local-regional therapy, 1 patient received combined chemotherapy, and 7 patients received regorafenib. Among all the patients, the incidence of grades 1 & 2 HFS was 46% and no grade 3 HFS was observed. The other main adverse events were hoarseness (35%), fatigue (27%), rash (27%), and neutropenia (15%). The most frequent adverse events from the CONCUR study and current analysis are shown in Table 1. Five patients (19%) had their treatment interrupted or their drug dose reduced due to adverse events. The median follow-up time of all patients was 5.3 (range, 1.6-13.1) months, the overall survival was not reached, and the median progression free survival was 2.9 (95% CI: 1.5-4.3) months. As the overall response in all patients after treatment, 3 cases (12%) achieved PR, 11 cases (42%) had SD and 12 cases (46%) showed PD. Conclusions: The addition of celecoxib to the cancer-line therapy regorafenib in CRLM patients did not reduce the incidence of HFS, but reduced the severity of HFS (grade 3). Also, it did not shorten the survival time of the patients. The addition of celecoxib to the main therapy might alleviate some adverse effects. [Table: see text]
ALBI and APRI score as prognostic factors for predicting the FABIB complications after liver resection in metastatic colorectal cancer.
Authors: Napolskaia Elena , Andabekov Timur , Sigua Badri , Rodina Maria , Khlobystina Alina , Gulo Elizaveta 
Published: June 2023

e15577 Background: Previous studies and this study demonstrate that liver resection, even with subsequent extrahepatic relapse, may be associated with long-term survival, are very encouraging for future studies of the effectiveness of liver cytoreduction in conditions of minimal extrahepatic disease. These data also contribute to selective cytoreduction in extrahepatic sites. If it is necessary to achieve an oncological result (maximally extended liver resection), sometimes the surgical result suffers in the form of postoperative complications. The most serious complication of liver resection due to colorectal cancer metastases is postoperative liver failure, characterized by high levels of INR and bilirubin by day 5 after surgery. Methods: To classify the most frequent postoperative complications, the FABIB system has been developed, which includes Failure, Ascites, Bile leakage, Infection, Bleeding. We tried to evaluate the possibilities of using the ALBI and APRI indicators as one of the factors that must be taken into account when predicting the development of complications from the FABIB group. ALBI score is used in predicting the development of liver failure in patients with hepatocellular cancer. APRI score is a predictor of fibrosis and cirrhosis in patients suffering from hepatitis. Results: We have analyzed the results of liver resections in 174 patients with metastatic liver damage in colorectal cancer. Among them 57% are women, 43% are men. Metastatic lesion of the right lobe – 38 (21.8%), the left lobe – 78 (44.8%), right and left lobes – 58 (33.4%). Right–sided tumors - 25% - 43 patients, left–sided tumors - 75% - 131 patients. According to the FABIB classification, liver insufficiency was observed in 25 patients (14%), ascites in 4 patients (2.3%), bile leakage in 8 (4.6%), infectious complications in 9 (5%), bleeding in 15 patients (8%). A single-factor analysis of the variance of ALBI and APRI indicators on the day of surgery, the day after surgery and on the 5th day after surgery did not show a statistically significant difference in the groups with all FABIB complications and without FABIB complications. However, statistical analysis separately in each subgroup of complications revealed a statistically significant difference in ALBI and APRI in the groups with and without postoperative liver failure, as well as a statistically significant difference in the groups with and without bleeding. Conclusions: Thus, it can be concluded that ALBI score and APRI score can be used in the early postoperative period to predict the development of postoperative liver failure and hemorrhagic complications not only in patients with hepatocellular cancer or cirrhosis, but also in patients with colorectal cancer with liver metastases. It could be useful in patients who have undergone several lines of chemotherapy before liver resection or with a large tumor lesion of the liver.
Predictors of response in advanced colorectal cancer (CRC) patients treated with immune-checkpoint inhibitors (ICI).
Authors: Benson Katherine K , Paul Samuel , Min Eric , Xu Menglin , Noonan Anne M. , Mittra Arjun , Malalur Pannaga G. , Roychowdhury Sameek , Jin Ning , Hays John L. , Elkhatib Rifat T. , Rahman Shafia , Miller Eric David , Diaz Pardo Dayssy Alexandra , Manne Ashish 
Published: June 2023

e15579 Background: ICI is reserved for mismatch repair (MMR) deficient and high tumor mutation burden (TMB) CRC patients in the current clinical practice. Identifying clinicopathological factors predicting response to ICI beyond MMR status could help effectively utilize ICI in this population. This is a retrospective review of advanced CRC (recurrent or metastatic) patients treated with ICI at an academic institute to identify the risk factors (RF) for poor outcomes. Methods: CRC patients who received at least one dose of ICI for between 1/1/2015 and 7/31/2021 at the Ohio State University were included in the study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, log-rank test rank test for survival outcomes, and logistic regression model for categorical outcomes using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort has 46 advanced patients (37 colon and 7 rectal), the median age was 51 years (range 26-82) with 52% females, 95% Caucasians, 76% had metastatic disease (47% and 32% had liver and lung metastases or mets, respectively), 41% were mismatch repair (MMR) deficient, and 30% had KRAS exon two mutations. About 30% and 43% got ICI in the first line and ≥ 4 lines, respectively. Most patients received pembrolizumab (57%), followed by nivolumab (28%), atezolizumab (11%), and durvalumab (4%). Chemotherapy and ICI combination was given in 39%. irAEs were reported in 19% (n = 9). Median overall survival (OS) and progression-free survival (PFS) were 37 months (m) (95% confidence interval [CI], 14-NR) and 15m (95% CI, 7-35), respectively. Baseline (before the first ICI dose) albumin (p = 0.005), hemoglobin or Hb (p = 0.001), and the red cell count or RBC (p = 0.003) were negatively related to OS, while platelet to lymphocyte ratio or PLR (p = 0.01) and alkaline phosphatase levels (p = 0.03) were positively related to OS. High BL white cell count (WBC) (p = 0.04), alkaline phosphatase or ALP (p = 0.01), and low albumin (p = 0.002) and alanine transferase or ALT (p = 0.005) significantly impacted the OS. Other significant predictors are discussed in the table below. Conclusions: Our study provides insights into baseline tumor characteristics (such as lung/liver mets, KRAS exon 2 mutations, and MMR status) and lab values (such as RBC, Hb, PLR, albumin, ALP, and ALT) that could predict tumor response in CRC patients treated with ICI. These associations must be validated in larger studies. [Table: see text]
Resection of primary colon cancer with and without resection of liver metastases: Propensity-score matched analysis.
Authors: Emile Sameh Hany , Horesh Nir , Garoufalia Zoe , Gefen Rachel , Zhou Peige , Wexner Steven D 
Published: June 2023

e15580 Background: Studies show that attempts to treat liver metastases during or before primary colonic cancer resection may improve survival. We aimed to compare overall survival of patients with colon cancer and liver metastases who underwent primary tumor resection with/without resection of liver metastases. Methods: This retrospective cohort study included patients with stage IV colon adenocarcinoma and isolated liver metastases who underwent surgical resection, using data from the National Cancer Database between 2015-2019. Patients with metastases to other organs or who did not have primary tumor resection were excluded. The cohort was divided into Colectomy-only (resection of primary colonic cancer only) and Colectomy-plus (resection of primary tumor and liver metastases) groups. After comparing, significant baseline and treatment confounders were identified and groups were matched using the nearest neighbor, 1:1 propensity-score method. Primary outcome was overall survival; secondary endpoints were short-term mortality and 30-day unplanned readmission. Results: 6780 patients who underwent primary tumor only resection and 4082 who underwent primary tumor and liver metastases resection were included. Patients in the Colectomy-only group were significantly older (63.73±13.59 vs 59.56±13.32 years;p < 0.001), more often male (56% vs 53.5%;p = 0.01), had more comorbidities (Charlson score 3: 4.4% vs 3.3%;p = 0.001) and right-sided colonic cancer (45.7% vs 43.2%;p = 0.002), shorter time before surgery (10 vs 30 days;p < 0.001), and more laparoscopic surgery (40.4% vs 35%;p < 0.001). Colectomy-only group patients had less chemotherapy (48.6% vs 50.7%, p = 0.04) and immunotherapy (34.1% vs 40.6%, p < 0.001) whereas Colectomy-plus group patients had more neoadjuvant systemic therapy (18.8% vs 10.2%;p < 0.001). Median overall survival of the Colectomy-plus group was significantly longer than Colectomy-only group (45.1 vs 24.4 months; p < 0.001). After matching for significant confounders, 2038 patients were included in each group. There were no significant differences between the two groups in 30-day (3.8% vs 3.1%;p = 0.3) and 90-day mortality (7.7% vs 6.6%;p = 0.2). Colectomy-plus group patients had significantly higher 30-day unplanned readmissions (7.2% vs 5.3%, p = 0.02) and significantly longer median overall survival (41.5 vs 28.4 months, p < 0.001). On Cox-regression analysis, resection of liver metastases and primary colonic tumor was associated with 33% mortality reduction (HR: 0.678, 95%CI: 0.618-0.745, p < 0.001). Conclusions: Resection of colonic cancer liver metastasis with the primary tumor is associated with significant survival benefit and may prolong survival by approximately 12 months, versus primary tumor resection alone. Synchronous resection of the primary tumor and liver metastases should be considered as it appears to offer survival benefit.