bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer (LARC) with or without oxaliplatin (OX): Individual patient data (IPD) meta-analysis of three randomized controlled trials (RCTs) with subgroup analyses of age cohorts.
Authors: Fontana Elisa , Zichi Clizia , Smyth Elizabeth Catherine , Mauer Murielle E. , Roedel Claus , Fokas Emmanouil , Hofheinz Ralf Dieter , Arnold Dirk , Schmoll Hans-Joachim , Van Cutsem Eric , Haustermans Karin , Stein Alexander , Gerard Jean-Pierre , Conroy Thierry , Jouffroy-Zeller Claire , Moehler Markus H. , Lordick Florian , Ben-Aharon Irit , Di Maio Massimo ,   Adolescent and Young Adult Gastrointestinal Task Force, EORTC
Published: May 2020

4074 Background: Neoadjuvant CRT with fluoropyrimidine (FP) is standard treatment for LARC, which is increasing in younger patients (pts). RCTs examining the addition of OX are still controversial. A post hoc analysis of the CAO/ARO/AIO-04 trial showed significant benefit in pts < 60y. We hypothesised that younger pts with LARC might have improved outcomes with OX-CRT. Methods: Systematic review and IPD meta-analysis were performed. Data from 3 RCTs (CAO/ARO/AIO-04, ACCORD-12, PETACC-6) testing the addition of OX to standard FP-based CRT in LARC were available (of 9 RCTs identified). Primary endpoint: disease-free survival (DFS), secondary endpoints: pathologic complete response (pCR), overall survival (OS). Analyses were by intention to treat (ITT), stratified by trial. Age cut-offs were 60y and 50y. Given the focus on young age a multivariate analysis evaluating all possible confounders was not intended in the current work. Results: IPD from 2914 pts were included (48.5% of available literature). Median age was 63; 70% were male; 79% had a performance status = 0; 72% were stage ≥III. In ITT (Hazard Ratio [HR] 0.88, 95%CI 0.77-1.01, p = 0.06), DFS was not significantly improved by the addition of OX (Table). In < 60y (n = 1166, 40% total), DFS was significantly improved by OX (HR 0.77, 95%CI 0.62-0.96, p = 0.02). In < 50y (n = 350, 12% total) there was a numerically better DFS, although not significant (HR 0.73, 95%CI 0.49-1.08, p = 0.12). Interaction test between age and DFS was non-significant (60y p = 0.11; 50y p = 0.44). In ITT, OX increased pCR from 13% to 16% (Odds Ratio [OR] 1.28, 95%CI 1.04-1.57, p = 0.024 [stratified by trial]), without significant interaction with age (60y p = 0.11, 50y p = 0.74). No OS benefit was demonstrated (HR 0.97, 95%CI 0.82-1.15, p = 0.75). Conclusions: This first IPD meta-analysis of three RCTs evaluating the addition of OX to CRT did not show significant interaction of OX with age. However, we confirm a signal for DFS benefit in pts < 60y and a non-significant increment in DFS in < 50 y although this analysis may be underpowered. Stage-stratified analyses and feasibility/toxicity data in age cohorts will be presented. [Table: see text]
Tumor mutational load, microsatellite instability and actionable mutations in metastatic colorectal cancer: Results from the TRIBE2 study.
Authors: Antoniotti Carlotta , Marmorino Federica , Lonardi Sara , Corti Francesca , Rossini Daniele , Moretto Roberto , Ugolini Clara , Giordano Mirella , Tamburini Emiliano , Santini Daniele , Aprile Giuseppe , Bordonaro Roberto , Zucchelli Gemma , Fontanini Gabriella , Lenz Heinz-Josef , Falcone Alfredo , Korn Wolfgang Michael , Cremolini Chiara 
Published: May 2020

4077 Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD. We performed a comprehensive NGS analysis of samples from randomized patients in order to investigate the prognostic impact of tumor mutational load (TML), its additional value with respect to the assessment of microsatellite instability (MSI), and the overall prevalence of potentially actionable alterations. Methods: Tumor DNA was obtained from formalin-fixed, paraffin-embedded blocks from primary tumors of 296 (44%) out of 679 randomized patients and underwent NGS analysis using the Caris MI TumorSeek panel, assessing 592 genes. TML was defined low, intermediate or high if < 7, 7-16 or > 16 mutations/Mb were found. MSI status was determined both by NGS and by IHC. Results: TML and MSI were successfully determined by NGS in 224 (76%) cases. NGS and IHC results were concordant in 221 (99%) cases. TML was low, intermediate or high in 56 (25%), 157 (70%) and 11 (5%) cases, respectively. When compared with TML low and intermediate tumors, TML high were more frequently right-sided (p = 0.013), mucinous (p < 0.001) and MSI-high (p < 0.001). TML high tumors were MSI-high or MSS in 8 (73%) and 3 (27%) cases, respectively. Two out of 3 TML high and MSS tumours showed a pathogenic POLE mutation (p.S459F and p.P286R). The other TML high, MSS and POLE wt tumor was dMMR at IHC (loss of MSH6 expression) and showed a pathogenic MSH6 mutation (p.F1040fs). As compared with low and intermediate TML, high TML was associated with longer PFS (median PFS: 17.3 vs 10.6; HR: 0.54 [95%CI: 0.35-1.09], p = 0.098) and OS (median OS: not reached vs 23.7: HR: 0.45 [95%CI:0-28-1.13], p = 0.106). No interaction effect between TML and treatment arm was observed, and no difference between TML low and intermediate tumors was reported in terms of baseline characteristics and prognosis. Actionable alterations ( HER2 mutations [N = 2] and amplifications [N = 4], KRAS G12C [N = 10] and BRAF V600E mutation [N = 39]) were found in 55 (19%) out of 296 cases. No NTRK/ROS/ALK or MET amplification was found. Conclusions: TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs.
Intra-tumoral microbes and overall survival in colorectal cancer patients.
Authors: Malalur Pannaga G. , Mo Xiaokui , Hoyd Rebecca , Carbone David Paul , Spakowicz Daniel 
Published: May 2020

4083 Background: The presence of certain bacteria among or adjacent to tumor cells may contribute to colorectal cancer (CRC) development. However, the effect of the tumor microbiome on survival in CRC patients undergoing treatment is poorly understood. We hypothesize that intra-tumoral microbes correlate with overall survival (OS) in CRC patients. Methods: We obtained RNA-seq data from CRC tumor biopsies from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. Results: The analyzed cohort included 99 CRC patients with an age range from 31-83 years, 62% female, and 44% with metastatic CRC. Therapies received prior to sample collection were grouped into chemotherapy with or without radiation (37%), antiVEGF/EGFR therapies (33%), no systemic therapy (23%), immunotherapy (3%); 3% were unknown. Overall, eleven bacteria were significantly associated with shorter OS, including a species in the genus Clostridium and Vibrio. Conversely, five other bacteria including several commensal gut microbes, were associated with longer OS. In patients who received chemotherapy with or without radiation (n = 38), several microbes were significantly associated with shorter OS, including a member of the genus Streptomyces. Only three bacteria were significantly associated with longer OS. In the patients who received antiVEGF/EGFR therapies (bevacizumab, cetuximab, panitumumab) (n = 33), several bacterial taxa were associated with shorter OS. In addition, bacteria including a member of the genera Bacillus and Staphylococcus were significantly associated with metastatic CRCs. (p < 0.05 for all, Fisher’s Exact tests). Conclusions: This study suggests that demonstrating the presence or absence of certain microbes in tumor biopsies could have important therapeutic implications for CRC patients. Only bacteria (no fungi, viruses, archaea, etc.) were found to significantly associate with OS across the entire cohort and within treatment subsets. The presence of bacteria was mostly, but not always, associated with worse OS. Antibiotics targeted towards bacterial species associated with negative outcomes could have the potential to improve OS in CRC patients.
Inpatient mortality, healthcare resource utilization, and complications of elective laparoscopic versus open colectomy in colon cancer patients: A nationwide inpatient sample analysis.
Authors: Vohra Ishaan , Katiyar Vatsala , Attar Bashar , Lingamaneni Prasanth , Moturi Krishna Rekha , Singh Sunny R K , Malapati Sindhu Janarthanam , Farooq Muhammad Zain , Gupta Shweta 
Published: May 2020

4109 Background: Laparoscopic colectomy (LC) has become an accepted safe and alternative technique to open surgical colectomy (OC) as a treatment option for colon cancer. We compared inpatient mortality, hospital resource utilization and complications in patients who underwent LC vs OC. Methods: All patients with known diagnosis of colon cancer who underwent elective colonic resection were identified using Nationwide Inpatient Sample (NIS) 2017. Univariate and multivariate linear and logistic regression was performed to compare the outcomes of patients who underwent LC vs OC. Results: In our cohort, 171, 480 adult patients with colon cancer were identified. The number of males and females were equal. The mean age was 67.2 years. They were predominantly Caucasians (67.6%). OC was performed on 3,869 patients. Of 1,345 patients who underwent LC, 385 were converted to OC. As compared to OC, LC was associated with lower postoperative complications including anastomotic leak, stricture, intestinal obstruction(1% vs 10.8%, p<0.01), blood transfusion(2.2 % vs 11.2% p=0.01), malnutrition(0.2% vs 4.4% p=0.02), shock(0.7% vs 1.8%,p=0.04), ICU care(1.9% vs 5.3%), mean length of stay (5.9 days vs 8.7 days, p=0.01), lower hospital charge (88,642$ vs 106,315 $,p<0.01) and lower mortality(0.3% vs 1.9%(p=0.02). There was a trend towards decreased venous thromboembolism (0.3% vs 1.7 %, p=0.9) and post-operative ileus (0.1% vs 0.7% p=0.60) in LC as compared to OC. On multivariate analysis, independent predictors of undergoing LC were younger age, teaching and large bed-sized hospital and lower Charlson comorbidity index. Race, insurance status and income had no significant association with selection of operative approach (Table). Conclusions: In our cohort, laparoscopic colectomy was found to have better peri and post-operative clinical outcomes including decreased inpatient mortality and hospital resource utilization. It should be promoted as the curative surgical option for colon cancer whenever clinically indicated. [Table: see text]
Early ileostomy closure is safe and feasible during adjuvant chemotherapy after total mesorectal excision surgery for rectal cancer.
Authors: Gu Xiaodong , Zhou Minwei , Wang Zihao , Li Zhenyang , Yang Yi , Zang Yiwen , Zhou Yiming , Xiang Jianbin , Chen Zongyou 
Published: May 2020

4111 Background: The aim of this study was to evaluate the comparative clinical and oncological outcomes of temporary ileostomy closure during or after adjuvant chemotherapy in patients with total mesorectal excision (TME) for rectal cancer. Methods: This randomized controlled trial investigated 87 patients (51 males, 36 females) with rectal cancer undergoing TME surgery with temporary ileostomy from January 2016 to December 2018. Patients were randomized divided into 2 groups: early group (43 patients, mean age: 60.35) who underwent stoma closure during adjuvant chemotherapy (3 months after primary surgery) and late group (44 patients, mean age 61.80) who underwent stoma closure after adjuvant chemotherapy (6 months after primary surgery). Both clinical and oncological outcomes were analyzed. Results: No significant differences were observed in operative time, blood loss, postoperative hospital stay, postoperative complications or hospital costs in ileostomy closure between the 2 groups. Stoma-quality of life (QOL) of patients in early group was significantly better than late group (52.02±5.68 vs 46.91±5.68, P <0.05). No significant difference in overall survival (P = 0.702) or progression-free survival (P = 0.638) was observed between the 2 groups. Conclusions: Ileostomy closure during adjuvant chemotherapy was clinically safe, and interruption of chemotherapy due to ileostomy closure did not change oncologic outcomes. Early ileostomy closure can improve QOL in those patients. Clinical trial information: NCT02665026 .
The landscape of MAP3K1/MAP2K4 alterations in gastrointestinal (GI) malignancies.
Authors: Stein Matthew K , Elliott Andrew , Hwang Jimmy J. , Lou Emil , Khushman Moh'd M. , Scott Aaron James , Marshall John , Sohal Davendra , Weinberg Benjamin Adam , Goldberg Richard M. , Salem Mohamed E. , Korn Wolfgang Michael , Grothey Axel 
Published: May 2020

4113 Background: Inactivating alterations in MAP3K1/MAP2K4 occur in various solid tumors, sensitize cancer models to MEK inhibitors, and have co-mutation partners which may enable therapeutic targeting. Methods: We retrospectively reviewed 20290 GI malignancy patients (pts), comprised of 9986 colorectal carcinoma (CRC) and 10304 non-CRC, whose tumors were profiled with Caris Life Sciences from 2015-2019. Profiling included immunohistochemistry (IHC) with programmed death ligand-1 (PD-L1), next-generation sequencing (NGS), tumor mutational burden (TMB) and deficient mismatch repair or microsatellite instability-high status (dMMR/MSI-H). Results: MAP3K1/MAP2K4-alteration ( MAP3K1/MAP2K4-MT) was more frequent in CRC than non-CRC pts (2.0% v. 1.2%, p<0.0001), with truncating mutations representing the majority of lesions along both genes. While MAP3K1/MAP2K4-MT CRC pts were similar in age and gender to wild-type (WT), mutated non-CRC pts were older (median age 69 v. 65 years) and more likely female (51% v. 42%) compared to WT (both p<0.05). MAP3K1/MAP2K4-MT CRC (25% v. 7%) and non-CRC (30% v. 3%) were more frequently dMMR/MSI-H than WT pts (both p<0.0001). MAP3K1/MAP2K4-MT CRC cases were affiliated with higher TMB and similar rate of PD-L1 expression compared to WT. A higher rate of MAP3K1/MAP2K4-MT CRC pts were right-sided (36% v. 22%, p<0.0001) and transverse (8% v. 4%, p<0.05) compared to WT, whereas a higher frequency of WT cases were left-sided (20% v. 28%, p<0.05) and rectal (15% v 23%, p<0.05). Of microsatellite stable (MSS) CRC pts, those with MAP3K1/MAP2K4-MT were more likely PIK3CA (26% v. 17%) and APC (85% v. 78%) and less-likely TP53 (64% v. 77%) co-mutated versus WT MSS pts (all p<0.05); no difference was seen in BRAF V600E, ERBB2/ ERBB3 or KRAS co-mutation rate in MSS pts. In both all-comers and MSS CRC, MAP3K1/MAP2K4-MT pts were more frequently co-mutated than WT with ARID1A, POLE, ATM, BRCA2 and PIK3R1 (all ≥7% of MAP3K1/MAP2K4-MT pts, p<0.0001). A higher frequency of all-comer non-CRC GI malignancy pts with MAP3K1/MAP2K4-MT were co-mutated with PIK3CA (13% v. 6%), ERBB2/ERBB3 (8% v. 3%) or APC (13% v. 5%) compared to WT (all p<0.01). For MSS non-CRC GI cases, ARID1A (50% v. 30%) and SMAD4 (21% v. 12%) were more frequently co-mutated in MAP3K1/MAP2K4-MT versus WT pts (all p<0.05). Conclusions: Truncating MAP3K1/MAP2K4 alterations occur in nearly 2% of GI malignancy pts and are more commonly associated with dMMR/MSI-H than WT. Potentially targetable co-mutation partners implicated in MAPK and PI3K pathways as well as POLE, BRCA2 and ATM warrant further evaluation.
SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA).
Authors: Sohal Davendra , Duong Mai T. , Ahmad Syed A. , Gandhi Namita , Beg Muhammad Shaalan , Wang-Gillam Andrea , Wade James Lloyd , Chiorean Elena Gabriela , Guthrie Katherine A , Lowy Andrew M. , Philip Philip Agop , Hochster Howard S. 
Published: May 2020

4504 Background: Clinical outcomes after curative treatment of resectable PDA remain suboptimal. To assess the potential of early control of systemic disease with multiagent peri-op CTx, we conducted a prospective trial in the National Clinical Trials Network. Methods: S1505 was a randomized phase II trial of peri-op CTx (12 weeks pre-, 12 weeks post-op) with either mFOLFIRINOX (Arm 1) or Gem/nabP (Arm 2). Eligibility required confirmed tissue diagnosis of PDA, ECOG PS 0 or 1, and resectable disease per Intergroup criteria. Primary outcome was 2-year overall survival (OS), using a “pick the winner” design; for 100 eligible patients (pts), accrual up to 150 pts was planned to account for cases deemed ineligible at central radiology review. We previously presented data on eligibility (ASCO 2019 abstr 4137). Here we present the final efficacy and toxicity results for the eligible pts. Results: From 2015 to 2018, 147 pts were enrolled; there were 102 eligible pts; 55 in Arm 1; 47 in Arm 2. For Arms 1 and 2 respectively: median age, 66 (44-76) and 64 (46-76) years; males, 36 (65%) and 24 (51%); and ECOG PS 0, 34 (62%) and 31 (66%) pts. Treatment details are shown in Table. For Arm 1 and Arm 2, respectively: Two-year OS was 41.6% and 48.8%; median OS was 22.4 months and 23.6 months. Neither arm’s 2-year OS estimate was statistically significantly higher than the a priori threshold of 40% (p=0.42 in Arm 1 and p=0.12 in Arm 2). Median disease-free survival (DFS) after resection was 10.9 months in Arm 1 and 14.2 months in Arm 2 (p=0.87). Conclusions: We have demonstrated: 1) two-year OS of 41.6% (median 22.4 months) with mFOLFIRINOX and 48.8% (median 23.6 months) with Gem/nabP for all eligible pts starting treatment for resectable PDA; 2) post-resection DFS of 10.9 months and 14.2 months, respectively; 3) adequate safety and high resectability rates with peri-op CTx; 4) little evidence that either regimen improves OS compared with the historical standard. Clinical trial information: NCT02562716 . [Table: see text]
Apatinib as second-line therapy in Chinese patients with advanced hepatocellular carcinoma: A randomized, placebo-controlled, double-blind, phase III study.
Authors: Li Qiu , Qin Shukui , Gu Shanzhi , Chen Xiaoming , Lin Lizhu , Wang Zishu , Xu Aibing , Chen Xi , Zhou Cuncai , Ren Zhenggang , Yang Lin , Xu Li , Bai Yuxian , Chen Lei , Li Jun , Pan Hongming , Cao Bangwei , Fang Weijia , Yan Ping , Jin Chunlei 
Published: May 2020

4507 Background: Chinese patients (pts) account for more than 50% of hepatocellular carcinoma (HCC) cases in the world and have special features in etiology, biological behavior, treatment strategy and prognosis. The aim of this study was to evaluate the efficacy and safety of apatinib, an inhibitor targeting vascular endothelial growth factor receptor-2, in Chinese pts with pretreated advanced HCC. Methods: In this randomized, placebo-controlled, double-blind, phase 3 trial done in 31 sites in China, pts with HCC who had received at least one line of systemic therapy (including sorafenib and oxaliplatin-based chemotherapy, which is another first-line standard-of-care in China) and had Child-Pugh liver function class A or B ≤7 points were enrolled. The pts were randomly assigned (2:1) to receive 750 mg apatinib orally once daily or placebo and stratified by ECOG performance status (0 or 1), previous sorafenib treatment (yes or no), and extrahepatic spread and/or macrovascular invasion (yes or no) in 28-day treatment cycles. The primary endpoint was overall survival (OS). Results: Between Apr 01, 2014 and May 03, 2017, 393 pts were randomized and received at least one dose of study treatment (261 in apatinib arm and 132 in placebo arm). The median OS was significantly longer with apatinib than that with placebo (8.7 months [95% CI 7.5-9.8] vs 6.8 months [95% CI 5.7-9.1]; hazard ratio 0.785 [95% CI 0.617-0.998]; p=0.0476). Pts in the apatinib arm also had prolonged median progression free survival (PFS) compared with those in the placebo arm (4.5 months [95% CI 3.9-4.7] vs 1.9 months [95% CI 1.9-2.0]; hazard ratio 0.471 [95% CI 0.369-0.601]; p˂0.0001). The objective response rate was 10.7% (95% CI 7.2-15.1) with apatinib versus 1.5% (95% CI 0.2-5.4) with placebo. Treatment-related adverse events (TRAEs) were reported in 250 (97.3%) pts in the apatinib arm and 92 (70.8%) pts in the placebo arm. The most common TRAEs of grade 3 and 4 were hypertension (71 [27.6%] pts in the apatinib arm vs 3 [2.3%] pts in the placebo arm), hand-foot syndrome (46 [17.9%] vs 0), decreased platelet count (34 [13.2%] vs 1 [0.8%]), and decreased neutrophil count (27 [10.5%] vs 0). 24 (9.3%) pts with apatinib and 13 (10.0%) pts with placebo died due to adverse events, and none were deemed treatment-related by investigators. Conclusions: Apatinib significantly prolonged OS and PFS in Chinese pts with pretreated advanced HCC, and was well tolerated with a manageable safety profile. Clinical trial information: NCT02329860 .
Phase III APACT trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P + Gem) versus gemcitabine (Gem) alone for patients with resected pancreatic cancer (PC): Outcomes by geographic region.
Authors: Reni Michele , Riess Hanno , O'Reilly Eileen Mary , Park Joon Oh , Hatoum Hassan , Saez Berta Laquente , Salminen Tapio , Oettle Helmut , Lopez Rafael , Dowden Scot D. , Karthaus Meinolf , Tabernero Josep , Van Cutsem Eric , Philip Philip Agop , Goldstein David , Berlin Jordan , Tempero Margaret A. 
Published: May 2020

4515 Background: The APACT trial was one of the largest and most geographically diverse trials of adjuvant chemotherapy for resected PC, allowing for comparison of outcomes by geographic region. In this analysis, we report updated overall survival (OS) results for the intent-to-treat (ITT) population and examine outcomes by geographic region. Methods: Treatment-naive patients with histologically confirmed PC, macroscopic complete resection, Eastern Cooperative Oncology Group performance status 0 or 1, and carbohydrate antigen 19-9 < 100 U/mL were eligible. Stratification factors were resection status (R0/R1) and lymph node status (positive/negative). Treatment was initiated ≤ 12 weeks postsurgery. Patients received nab-P 125 mg/m2 + Gem 1000 mg/m2 or Gem 1000 mg/m2 on days 1, 8, and 15 of six 28-day cycles. The primary endpoint was disease-free survival by independent review. Secondary endpoints were OS and safety. Results: The updated OS analysis (data cutoff date, January 2020) revealed a median OS of 41.8 months with nab-P + Gem compared with 37.7 months with Gem alone (hazard ratio [HR] 0.81; 95% CI, 0.68 - 0.97; nominal P = 0.047; Table). In each geographic region, the median OS with nab-P + Gem was numerically longer than with Gem alone. Conclusions: The updated OS analysis of the ITT population supports the previously reported trend favoring nab-P + Gem. The geographic regional analyses reveal numerically longer OS with nab-P + Gem vs Gem alone and variable outcomes by region; however, the differences do not support the trend observed in the ITT population, potentially due to limited sample sizes. Registration: EudraCT (2013-003398-91). Clinical trial information: NCT01964430 . [Table: see text]