bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab plus S-1 and raltitrexed for refractory metastatic colorectal cancer.
Authors: Chen Ye , Liu Jiyan , Gou Hongfeng 
Published: May 2020

e16024 Background: There are lack of effective drugs and regimens for refractory metastatic colorectal cancer (mCRC), especially in China. Dihydropyrimidine dehydrogenase (DPD) is the rate limiting enzyme of 5-FU catabolic pathway. Thymidylate synthase (TS) is the target of 5-FU anti-tumor mechanism. Several studies have shown the up-regulation of the two enzymes after the use of 5-FU in colorectal cancer, which may be closely related to the 5-FU resistance. The preliminary research of our center has shown the efficacy and safety of S-1 (containing a DPD inhibitor) plus raltitrexed (a TS inhibitor) in refractory mCRC. The aim of this study is to evaluate the efficacy and safety of bevacizumab plus S-1 and raltitrexed for patients with mCRC after failure to fluoropyrimidine, irinotecan and oxaliplatin. Methods: This study is a one-center, single-arm, prospective phase II trial, being carried out in the Cancer Center, West China Hospital, Sichuan University, China. The patients who have progressed after the treatment of fluoropyrimidine, irinotecanand oxaliplatin, have at least one measurable lesion according to RECIST 1.1 criteria were enrolled. Patients receive bevacizumab 7.5mg/kg and raltitrexed 3 mg/m2 on days 1 plus S-1 80, 100 or 120 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Results: From Sep 2015 to Nov 2019, 44 patients were enrolled. By Feb 5, 2020, eleven patients were alive. Tumor response evaluation was available in 44 patients at the time of the analysis. There was no complete response, ORR was 15.9%(7/14) and disease control rate was 54.5%(24/44). mPFS and mOS were 110 days (95% confidence interval, 65.0-155.0) and 367 days (95% confidence interval, 310.4-423.6). The most common adverse events were bone marrow depression, dysfunction of digestive system abnormality of liver function and bleeding. Most of these adverse events were mild to moderate. Conclusions: Bevacizumab plus S-1 and raltitrexed further showed its moderate effect for refractory mCRC. Most of the adverse effects were mild to moderate, which could be well controlled. This combined regimen is worthy of further study as third or later line therapy in mCRC. Clinical trial information: ChiCTR1900020485 .
Efficacy of single-agent epidermal growth factor receptor inhibition in the second-line setting for metastatic colorectal cancer with a goal towards retreatment strategies.
Authors: Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Uboha Nataliya Volodymyrivna , Deming Dustin A. 
Published: May 2020

e16035 Background: Advances in the understanding of colorectal cancer (CRC) biology, including clonal evolution are leading to novel treatment strategies. Epidermal growth factor receptor inhibition (EGFRi) with cetuximab or panitumumab has shown significant clinical utility in KRAS/NRAS/BRAF wildtype (wt) CRC. These inhibitors are most commonly used in the third-line treatment setting in the United States. Upon the development of resistance to EGFRi, withdrawal of the EGFR inhibitor can lead to decay of resistant clones allowing for EGFR inhibitor retreatment in additional lines of treatment. Earlier-line use of single agent EGFRi could allow more patients to utilize a retreatment strategy, however no large prospective clinical trials have assessed the clinical activity of second line EGFRi in the setting of molecular selection. Here, we assess the clinical outcomes of EGFRi monotherapy for advanced KRAS wt CRC after initial progression on a single line 5FU based chemotherapy. Methods: A retrospective chart review examined patients who received single agent EGFRi in KRAS wt CRC in the second line setting. Line of therapy was defined at time of metastatic disease or recurrence within 6 months of adjuvant therapy. Clinical outcomes of overall response rate (ORR) and progression free survival (PFS) were assessed per RECIST v1.1. Results: 20 cases were identified who received single agent EGFRi (panitumumab or cetuximab) as monotherapy in the second line setting. All pts received prior 5FU based chemotherapy. Reasons for using EGFR inhibitor monotherapy in this setting included to avoid toxicities from prior chemotherapy (largely immunosuppression and GI toxicities), bridge from recent operative management, or maintain functional performance status. Patients had median age of 62 [45, 89] and majority with ECOG PS 0-1 (78.5% of those reported). Best responses included complete response 7%, partial response 21%, stable disease 64% and progressive disease 7%, and a disease control rate of 93%. The 6 and 8 month PFS were 70% and 50%, respectively. PFS ranged from 1.5 to 17.3 months with median PFS 8.2 ± 3.6 months. Conclusions: This work demonstrates preliminary efficacy data to use single agent EGFRi in the second-line setting for KRASwt patients with CRC. Future investigations will aim to prospectively validate the benefit of this treatment strategy to facilitate EGFRi retreatment and improve patient survival.
LM02-trial perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases.
Authors: Piringer Gudrun , Gruenberger Thomas , Kuehrer Irene , Oefner Dietmar , Kaczirek Klaus , Laengle Friedrich , Viragos-Toth Istvan Levente , Amann Arno , Eisterer Wolfgang , Fuegger Reinhold , Andel Johannes , Pichler Angelika , Stift Judith , Soelkner Lidija , Gnant Michael , Thaler Josef 
Published: May 2020

e16046 Background: Nearly half of patients with colorectal cancer develop liver metastases and only 20% are initially resectable. Surgical resection of liver metastases results in five-year survival rates of 24-48%. Perioperative FOLFOX therapy increases progression free survival. In advanced disease the addition of targeting therapies to chemotherapy results in an overall survival advantage. In this study the efficacy and safety of perioperative panitumumab and FOLFIRI therapy were investigated. Methods: Patients with previously untreated, wild-type RAS, potentially resectable colorectal cancer liver metastases were included. Chemotherapy consisted of irinotecan 180mg/m2 intravenously over 120 minutes and fluorouracil bolus 400mg/m2 intravenously, followed by a 46 h infusion of fluorouracil 2400mg/m2 repeated every 2 weeks. Panitumumab was given as an intravenous dose of 6mg/kg every 2 weeks. Preoperative 4 cycles and postoperative 8 cycles were administered. Primary objectives were the evaluation of efficacy and safety. Results: We enrolled 36 patients in 7 centers in Austria. ITT-analyses included 35 patients. There were 28 men and 7 women, the median age was 66 years. 91.4% completed the planned 4 cycles of preoperative therapy and 82.9% underwent liver resection. R0 resection rate was 82.7%. 20 patients started postoperative chemotherapy and 12 patients completed the planned 8 cycles. Objective response rate after preoperative therapy was 65.7% with one radiological complete remission and 22 partial remissions. In 20% and 5.7% of patients stable disease and progressive disease were documented, respectively. Three patients discontinued preoperative treatment due to adverse events without response evaluation. The most common grade 3 adverse events were diarrhea (n = 4), rash (n = 3) and leukopenia (n = 3) during preoperative therapy. One patient died due to sepsis and one had a pulmonary embolism grade 4. After surgery two patients died due to hepatic failure and one patient had a suture related complication grade 3. Most common grade 3/4 adverse events during postoperative therapy were rash (n = 2), stroke (n = 1) and intestinal obstruction (n = 1). Conclusions: Panitumumab in combination with FOLFIRI as preoperative therapy for operable colorectal liver metastases in RAS wild-type patients results in a radiological objective response rate in 65.7% of patients with a manageable grade 3 diarrhea rate of 14.3%. Progression-free survival and overall survival are still monitored. Clinical trial information: 2012_000265-20 .
Health economic analysis of doublet chemotherapy with and without bevacizumab for first-line treatment of RAS mutant metastatic colorectal cancer based on real-world data.
Authors: Degeling Koen , Wong Hui-Li , Pereira-Salgado Amanda , Kosmider Suzanne , Wong Rachel , Tie Jeanne , Stefanou Greg , Nott Louise M. , Shapiro Jeremy David , Richardson Gary Edward , Gibbs Peter , IJzerman Maarten J. ,   TRACC Collaboration
Published: May 2020

e16048 Background: Bevacizumab remains the dominant biologic treatment option for RAS mutant (RASmt) metastatic colorectal cancer (mCRC). While the health economic impact of bevacizumab in the RASmt subpopulation may deviate from its use in the general mCRC population, this has never been investigated. This study uses the power of real-world data to assess the cost-effectiveness of doublet chemotherapy with compared to without bevacizumab (ChemBev and ChemOnly, respectively) for first-line treatment of RASmt mCRC, while accounting for subsequent treatment in second and third line. Methods: Data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was analyzed to populate a discrete event simulation of three treatment lines, surgery of primary tumor and metastases, hospitalizations following serious adverse events, and best supportive care. Imbalance in baseline patient and disease characteristics was corrected for in all analyses using inverse probability weights. Costs were included from an Australian public payer perspective in Australian dollars (AUD). All health and economic outcomes were discounted at 5% per year. Results: Of the 507 included RASmt mCRC patients that started first-line treatment in the 2010 – 2017 time period, 345 received ChemBev and 162 ChemOnly. The corrected median time on first-line treatment was 7.1 months (95% confidence interval: 6.4 – 8.0) for ChemBev and 4.1 months (3.5 – 5.1) for ChemOnly. Time on second- and third-line treatment was comparable between the groups. Corrected overall survival was 22.6 months (21.7 – 24.0) for ChemBev and 14.3 months (12.1 – 21.7) for ChemOnly. In terms of the health economic impact, mean life years were 1.9 for ChemBev and 1.5 for ChemOnly, and mean costs were AUD 93,025 and AUD 44,929 per patient, respectively. The resulting incremental cost-effectiveness ratio (ICER) of ChemBev compared to ChemOnly was AUD 149,317 per life-year gained (LYG). Conclusions: In contrast to results from clinical trials, overall survival was substantially longer for patients who received bevacizumab, which can possibly be attributed to an imbalance between groups despite correction for known prognostic factors. At an ICER of AUD 149,317 per LYG, the economic burden of upfront treatment with bevacizumab was found to be substantial and consistent with estimates for the general mCRC population. This is mainly caused by the duration of first-line treatment, which was significantly longer for ChemBev.
Clinically relevant multi-omic analysis of colorectal cancer.
Authors: von der Heyde Silvia , Krawczyk Margarita , Bischof Julia , Corwin Thomas , Frommolt Peter , Woodsmith Jonathan , Juhl Hartmut 
Published: May 2020

e16063 Background: Cancer is a highly heterogeneous disease, both intra- and inter-individually consisting of complex phenotypes and systems biology. Although genomic data has contributed greatly towards the identification of cancer-specific mutations and the progress of precision medicine, genomic alterations are only one of several important biological drivers of cancer. Furthermore, single-layer omics represent only a small piece of the cancer biology puzzle and provide only partial clues to connecting genotype with clinically relevant phenotypic data. A more integrated approach is urgently needed to unravel the underpinnings of molecular signatures and the phenotypic manifestation of cancer hallmarks. Methods: Here we characterize a colorectal cancer (CRC) cohort of 500 patients across multiple distinct omic data types. Across this CRC cohort, we defined clinically relevant whole genome sequencing based metrics such as micro-satellite-instability (MSI) status, and furthermore investigate gene expression at the transcript level using RNA-Seq, as well as at the proteomic level using tandem mass spectrometry. We further characterized a subgroup of 100 of these patients through 16s rRNA sequencing to identify associated microbiome profiles. Results: We combined these analyses with comprehensive clinical data to observe the impact of ascertained molecular signatures on the CRC patient cohort. Here, we report how patient survival correlates both with specific molecular events across individual omic data types, as well as with combined multi-omic analyses. Conclusions: This project highlights the utility of integrating multiple distinct data types to obtain a more comprehensive overview of the molecular mechanisms underpinning colo-rectal cancer. Furthermore, through combining identified aberrant molecular mechanisms with clinical reports, multi-omic data can be prioritized through their impact on patient cohort survival.
A new CRISPR mediated intestinal tumor mouse model targeting four canonical tumor suppressor genes.
Authors: Kashima Hajime , Veronese-Paniagua Daniel , Fischer Anthony , Madison Blair , Rubin Deborah 
Published: May 2020

e16064 Background: Mouse models of intestinal tumorigenesis have been developed and many of them involve mutations in the Apc gene. However, human intestinal tumors contain multiple additional sporadic mutations in tumor suppressor genes (TSGs). Our goal is to develop a novel mouse model of intestinal tumorigenesis that can recapitulate the natural history of mutations in diverse stages of tumor development. Methods: We used multiple guide RNAs to achieve random mutations in the canonical TSGs, Apc, Pten, Smad4, and Tp53. We generated transgenic (PPAS) mice that constitutively express the appropriate guide RNAs. Moreover, we achieved inducible Cas9 expression in icCas9N mice intestine using the Villin promoter to drive both a doxycycline-dependent activator and a doxycycline-inactivated repressor. We fed the doxycycline chow to PPAS:icCas9 double transgenic mice from the age of 6 to 8 weeks, and harvested intestine at 12 weeks. Results: We examined seven PPAS;icCas9 mice, and detected intestinal tumors in all the mice. Two mice had small intestinal tumor, three mice had colonic tumor, and two mice had tumors in both small and large intestine. The average number of tumors were 0.86, 1.57, 2.43 in small intestine, colon, and both respectively. We analyzed mutations in 11 tumors in 6 mice. The mutation patterns of Apc, Pten, Smad4 and Tp53 in tumors shared three distinct patterns. One was characterized by mutations in all four TSGs (n = 9). The second showed mutation in APC and Smad4 and Pten (n = 1). The third showed mutation only in Tp53 (n = 1). Normal intestine and colon in PPAS:icCas9 mice had no mutations. Conclusions: This model provides a powerful platform for modeling intestinal tumorigenesis driven by the canonical signaling pathway which are commonly dysregulated in colon cancer. This model provides a means for rapid development of intestinal tumors in mice, enabling an investigation of the relationship between novel candidate regulators of tumorigenesis and the canonical signaling pathways regulated by these four common TSGs. [Table: see text]
Assessing real-world outcomes in metastatic colorectal cancer with KRASG12C mutation.
Authors: Wong Hui-Li , Cui Wanyuan , Loft Matthew , Lee Margaret , Wong Rachel , Shapiro Jeremy David , Tie Jeanne , Lee Belinda , Cooray Prasad , Zimet Allan Solomon , Gibbs Peter , Solomon Benjamin J. , Desai Jayesh ,   TRACC Collaboration
Published: May 2020

e16072 Background: The KRASG12C mutation is present in 3% of colorectal cancer and is of particular interest given the recent development of specific targeting drugs. Previous data suggest KRAS (all) mutations may impact prognosis. Here we assess the clinical features and outcomes of real world patients with KRASG12C mutant metastatic colorectal cancer (mCRC) to explore any clinicopathologic associations and prognostic impact. Methods: Patients diagnosed with mCRC between January 2011 and December 2018 were included in this prospective mCRC registry. Patients with BRAF mutations, unknown or unspecified KRAS variants were excluded. Clinicopathologic features, treatment and overall survival (OS) were compared for RAS wildtype (RASWT) and KRASG12C mutant patients, and between KRASG12C and other (RASother) mutations. Results: Of 1308 patients analysed, 674 (52%) were RASmut, of whom 56 (8.3%) were KRASG12C. More patients with KRASG12C were female compared to RASother and RASWT (Table). No differences were observed in primary tumor location, number of metastatic sites and distribution of metastases. The proportion of patients undergoing metastasectomy was similar between KRASG12C and RASother, and KRASG12C and RASWT. There was no difference in the proportion of patients receiving systemic therapy. RASWT patients received more lines of therapy. Median OS was similar between KRASG12C, RASother, and RASWT: 31.7 vs 29.2 vs 31.8 months respectively (P = 0.545). Conclusions: KRASG12C mutations were observed in 4.3% of mCRC patients and in 8.3% of RAS mutant cases. Patients with KRASG12C have comparable clinical features to RASWT or RASother mCRC. Treatment and survival were also similar between groups. KRASG12C does not appear to be prognostic, but may be an important predictive biomarker as promising targeted therapies continue to be developed. [Table: see text]
Trends in colorectal cancer incidence in India.
Authors: Mathew Thomas Vinay , Baby Basil , Wang Kevin , Lei Feitong , Chen Quan , Huang Bin , Mathew Aju 
Published: May 2020

e16084 Background: Colorectal cancer (CRC) accounts for 10% of global cancer deaths yearly. It is postulated that the incidence rates are rising in developing countries like India. We present a comprehensive overview of colorectal cancer incidence in India from various regions from 2004 to 2014. Methods: We obtained data on CRC incidence from the Population Based Cancer Registries (PBCR) of the National Cancer Registry Program. We calculated age-standardized incidence rates (to WHO World Standard Population 2000) for five-year age groups for period of diagnosis (2004-05, 2006-08, 2009-11, and 2012-14). Results: From 2004 to 2014, CRC incidence rates in India increased by 20%. During 2004-2005, the incidence rate of CRC was 5.8 per 100,000 persons. It increased to 6.9 during 2012-2014. Conclusions: CRC rates are rising in India. Even though the absolute rates are low in the Indian population, the rising rates pose a problem in rising cancer morbidity in India. The rising rates can be attributed to changing lifestyles that include consumption of calorie-rich and low fibre diet, excessive use of red meat and processed foods, and physical inactivity. There is a need for cost-effective strategies to enable early diagnosis for colorectal cancer in India. Affordable and equitable treatment will help increase the 5-year survival rates of colorectal cancers. [Table: see text]
Predictive and prognostic factors of apatinib in metastatic colorectal cancer.
Authors: Wang Fen , Wang Shubin , Yuan Xia , Jia Jun , Bi Xiaoxia , Zhou Zeqiang , Zhou Qiming , Li Xia , Luo Changguo , Deng Minghui , Yi Liangjie , Li Yong , Lu Jianxin , Su Wenzhi , Chen Hanbin , Zhu Yu 
Published: May 2020

e16092 Background: It has been extremely challenging to identify suitable predictive or prognostic factors of anti-VEGF agents. Apatinib, a vascular endothelial growth factor receptor 2(VEGFR-2) inhibitor, showed promising efficacy in chemo-refractory metastatic colorectal cancer (mCRC) patients in a phase II trial. The aim of current study was to identify the potential predictive and prognostic factors of apatinib in this phase II trial. Methods: A total of 48 patients with mCRC who had failed from standard fluorouracil-containing chemotherapies were recruited in this prospective single-arm study. Apatinib at a 500mg dose was administered daily continuously. Clinical parameters, including patients background, biochemical parameters at baseline, tumor markers at baseline and day 28, and adverse events in initial 28 days were evaluated to identify predictive and prognostic factors. The median neutrophil/lymphocyte ratio (NLR) was adopted as a cutoff value to discriminate patients with low versus high NLR. Early tumor marker decrease was defined as an abnormal parameter with a decrease of > 10% by day 28. This study is registered with the Chinese Clinical Trial Registry, number ChiCTR1900020503. Results: Patients characteristics were not associated with differences in PFS and OS. Seven (14.6%) and 11 (22.9%) patients had initial normal CEA and CA19-9, respectively, and were excluded from the analysis of tumor markers. The median NLR were 4.1. In univariate analysis, low baseline NLR, early CA19-9 decrease, and the hand-foot syndrome (HFS) were associated with good progression-free survival (PFS) [NLR, HR 0.38 (95% CI 0.16–0.89), P = 0.027; CA19-9, HR 0.37 (95% CI 0.16-0.83), P = 0.016; HFS HR 0.23 (95% CI 0.08-0.68, P = 0.007); respectively]. Low baseline NLR and early CA19-9 decrease were also associated with good overall survival (OS) [NLR, HR 0.34 (95% CI 0.17–0.67), P = 0.002; CA19-9, HR 0.46 (95% CI 0.23-0.95), P = 0.035; respectively]. NLR and HFS retained a significant association with PFS [NLR, HR 0.36 (95% CI 0.15–0.84), P = 0.019; HFS, HR 0.25 (95% CI 0.08–0.77), P = 0.016; respectively] while only NLR retained a significant association with OS [NLR, HR 0.35 (95% CI 0.17–0.70), P = 0.019] in the multivariate analysis using the aforementioned factors. Conclusions: Clinical parameters including low baseline NLR, early CA19-9 decrease and HFS could be positive predictive factors of the efficacy of apatinib in mCRC. NLR could be the independent prognostic factor of OS in mCRC. Additional studies are warranted for further validation.