bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I multicenter, open-label study to establish the maximum tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin combination in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Hollebecque Antoine , Calvo Aitana , Andre Thierry , Argiles Guillem , Cervantes Andres , Leger Catherine , Valette Aude , Amellal Nadia , Fougeray Ronan , Tabernero Josep 
Published: January 2019

816 Background: Preclinical evidence suggests improved efficacy when combining trifluridine/tipiracil with oxaliplatin compared to each monotherapy (Nukatsuka, 2015). The primary objective was to determine the MTD and the safety profile of the doublet among mCRC pts who have progressed after at least one prior line of treatment. Methods: Using a 3+3 design, eligible pts received escalating trifluridine/tipiracil doses from 25, 30 to 35 mg/m² bid, days 1–5 q14, together with a fixed dose of oxaliplatin 85 mg/m² (day 1). An intermediate cohort with a lower dose of oxaliplatin (65 mg/m²) plus 35 mg/m² of trifluridine/tipiracil was also tested. Results: Fifteen of 17 enrolled pts were evaluable for DLTs. Median age was 61 years (range 32-74), 11 and 6 pts had an ECOG PS of 0 and 1, respectively; 76% received ≥2 lines including for 10 pts previous line with oxaliplatin. Pts received a median of four cycles (range 1–23). The MTD was defined at the maximal planned dose: trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m². Combination was well tolerated and only one DLT was observed (grade 3 febrile neutropenia). The most common ( > 20%) non-hematologic adverse drug reactions (ADRs) included nausea, asthenia, vomiting, diarrhea and decreased appetite. Moderate-to-severe neutropenia occurred in 5 pts and thrombocytopenia in 4 pts (all grade 1); 1 pt experienced a grade 4 anemia at Cycle 4. Oxaliplatin-related neurotoxicity grade ≥2 was observed in 2 pts. ADRs were manageable with basic supportive care, with treatment delays or temporary interruptions. Best overall response includes partial response (n = 1, unconfirmed), stable disease (n = 7). Conclusions: At the MTD (trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m²), incidence and severity of bone marrow suppression as well as gastrointestinal toxicities were similar to previously published data. A cohort of 6 additional pts will confirm the MTD. An expansion part combining the doublet with either nivolumab or bevacizumab evaluating the safety and preliminary antitumor activity of each triplet will start soon. Clinical trial information: NCT02848443.
FOLFIRI3-aflibercept as second- or later-line therapy in patients with metastatic colorectal cancer.
Authors: Carola Candice , Ghiringhelli Francois , Kim Stefano , Andre Thierry , Barlet Juliette , Bengrine Leila , Marijon Helene , Garcia Marie Line , Borg Christophe , Dainese Linda , Steuer Nils , Larsen Annette K , De Gramont Aimery , Chibaudel Benoist 
Published: January 2019

817 Background: The efficacy of the standard FOLFIRI-aflibercept second-line therapy may be improved by the chemotherapy regimen in metastatic colorectal cancer (MCRC). FOLFIRI was optimized by splitting the dose of irinotecan on day 1 and day 3 and by removing the bolus of 5-FU in the FOLFIRI3 regimen. Methods: This is a retrospective multicentric cohort, evaluating efficacy and safety of the association of aflibercept with FOLFIRI3, in patients (pts) with previously treated MCRC. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: From September 2014 to December 2016, 74 pts were treated in four French centers. Nine pts were excluded due to prior use of aflibercept (n = 3), more than one prior line of treatment in irinotecan-naïve pts (n = 3) and inadequate liver function (n = 3). In the cohort of irinotecan-naïve pts (n = 30), ORR and DCR were 43.3% and 76.7%. Median PFS and OS were 11.3 months (95% CI 6.1-29.0) and 17.0 months (95% CI 13.0-17.3). The most common ( > 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), hypertension (6.7%). In the cohort of pts previously treated with irinotecan (n = 35), 20 (57.1%) pts received ≥2 prior lines of treatment with various prior irinotecan regimen (FOLFIRINOX, n = 21; FOLFIRI, n = 10; FOLFIRI3, n = 4). ORR and DCR were 34.3% and 60.0%. Median PFS and OS were 5.7 months (95% CI 3.9-10.4) and 14.3 months (95% CI 12.8-19.5). In 4 patients refractory to irinotecan, FOLFIRI3-aflibercept led to one partial response, 2 stabilizations, and one patient not evaluable. Conclusions: A minimal modification of the FOLFIRI regimen led to a dramatically improvement of efficacy with FOLFIRI3-aflibercept, whatever prior use of irinotecan. Further randomized trial is planned.
Validation of the Mexican-Spanish version of the EORTC QLQ-INFO25 instrument in patients with gastrointestinal cancers.
Authors: Salas-Becerril Maricela , Allende-Perez Silvia R , Monroy Alejandra , Aiello-Crocifoglio Vincenzo , Onate-Ocana Luis F. 
Published: January 2019

818 Background: Information received by the cancer patient is a main component of an evaluation of quality of care. The most frequently used instrument to do so is the EORTC QLQ-INFO25, and our aim is to validate its Mexican-Spanish version in patients with gastrointestinal cancer. Methods: This is a prospective study including patients who responded the QLQ-INFO25 instrument at a cancer referral center. Reliability and validity tests were performed, and the association of scale scores with clinical variables is shown. Results: One hundred thirty six patients were included, 70 female and 66 males. Mean age was 56.2 years; 111 corresponded to colorectal and 25 to gastroesophageal cancer. Questionnaire compliance rates were high and both instruments were well accepted; no missing values were found. Convergent item correlation in the QLQ-C30 ranged from 0.223 to 0.822 and in the QLQ-INFO25 from 0.008 to 0.768, respectively. Divergent item correlation ranged from 0.011 to 0.674 and from 0.014 to 0.662, respectively. Cronbach’s α coefficients of eight of nine multi-item scales of the QLQ-C30 and all four multi-item scales of the QLQ-INFO25 instruments were > 0.7 (range, 0.655–0.905). Selected scales of both instruments distinguished among esophagogastric or colorectal cancer. Conclusions: The Mexican-Spanish version of the QLQ-INFO25 questionnaire provides domains not covered by the generic instrument, it is reliable and valid to be used in clinical trials assessing patients’ appraisal on the received information by the health personnel.
Impact of primary tumour location (PTL) on outcomes in patients (pts) with metastatic colorectal cancer (mCRC) undergoing first-line panitumumab (Pmab) + FOLFIRI treatment .
Authors: Karthaus Meinolf , Van Den Eynde Marc , Mineur Laurent , Thaler Josef , Koukakis Reija , Berkhout Marloes , Gallego Javier 
Published: January 2019

820 Background: Prognosis in pts with mCRC is affected by PTL; PTL may also affect the activity of the epidermal growth factor receptor inhibitor Pmab (+ FOLFIRI). Methods: In this phase II, single-arm study (NCT00508404), pts received first-line Pmab+FOLFIRI Q2W until disease progression (PD); primary endpoint: objective response rate (ORR). Analyses included pts with RAS wild-type (WT) mCRC (no mutations in KRAS/ NRAS exons 2, 3 and 4). Baseline demographics/disease characteristics were summarised by PTL and the effect of PTL on outcome was analysed. Early tumour shrinkage (ETS) was defined as a ≥30% reduction in the sum of the longest diameters of measurable target lesions at week 8. Depth of response (DpR) was the maximum % change from baseline to nadir in pts with shrinkage, or the change at PD in pts with no shrinkage. DpR was positive for shrinkage, negative for growth and zero for no change. Progression-free survival (PFS) was analysed by PTL and ETS status. There was no long-term follow-up of overall survival in this study. Results: PTL could be determined in 52/69 (75%) RAS WT pts; 45/52 (87%) had left (L)-sided disease. Pts with L- vs right (R)-sided disease were more likely to have BRAF WT mCRC (91% vs 71%), an ECOG performance status of 0 (56% vs 43%) and liver+other metastases (53% vs 29%). Pts with L- vs R-sided disease had longer median (95% CI) PFS (11.2 [7.6,17.0] vs 7.2 [1.1,19.1] months) and were more likely to experience ETS ≥30% (53% vs 29%). ORR (60% vs 57%), median (95% CI) duration of response (DoR; 13.2 [9.3,47.7] vs 14.3 [3.5,17.3] months), median DpR (61% vs 60%), and resection rates (any: 13% vs 14%; R0: 7% vs 14%) were similar for L- and R-sided pts. ETS ≥30% was associated with improved PFS irrespective of PTL (HR [95% CI] vs ETS < 30%: 0.53 [0.22,1.29] on L; 0.35 [0.03,3.54] on R). Conclusions: These post-hoc data are in line with larger previous studies suggesting improved ETS/PFS with Pmab treatment in RAS WT left-sided mCRC; ORR, DoR and DpR were similar regardless of PTL. No formal conclusions can be drawn regarding the activity of Pmab+FOLFIRI in right-sided mCRC due to the small pt numbers, but ETS may also predict PFS benefit in right-sided disease. Clinical trial information: NCT00508404.
Phase II dose titration study of regorafenib for patients with unresectable metastatic colorectal cancer that progressed after standard chemotherapy.
Authors: Kudo Toshihiro , Kato Takeshi , Kagawa Yoshinori , Sakai Daisuke , Satoh Taroh , Doki Yuichiro , Mori Masaki 
Published: January 2019

821 Background: The CORRECT study showed significant overall survival (OS) improvement in the regorafenib (REG), compared with the placebo group in metastatic colorectal cancer (mCRC) which progressed after standard chemotherapy. In Japanese subgroup analysis, the hazard ratio of OS also indicated a tendency similar to overall population. The standard starting dose of REG is 160mg/body/d, and not adjusted according to body weight and height, race of the patients, or other parameters, however, some cases require dose reduction to 120mg/d or less due to adverse events (AE). Dose modification due to AE was observed frequently in Japanese compared with non-Japanese during the study (84.6% and 51.3%). Therefore, we performed this dose titration study to investigate efficacy and safety of REG. Methods: This single arm, multicenter phase II study evaluated lower initial dose of REG (120mg/d, for 21 days, followed by 7-day break) in mCRC progressed after standard chemotherapy. Dose escalation to 160mg was allowed in 2nd and subsequent cycle, if patients developed < grade 2 AE, except for liver toxicity. Patients underwent radiographic evaluation every 8 wks. The primary endpoint was disease control rate (DCR: CR+PR+SD ≥ 6 wks). The major secondary endpoints included progression free survival (PFS), OS and safety. Results: Between September 10, 2015, and March 7, 2017, total 60 patients were enrolled into the study. Median age was 68.5 (range: 30-84), and ECOG PS 0/1 were 70%/30%. DCR was 36.7% (22/60); 7% (4/60) have had SD for 6 months or longer. Median PFS was 2.3 months (95% CI: 1.8 - 2.8). 3.3% of patients (2/60) had protocol defined REG dose escalation to 160mg; one case was from the cycle 2, and the other case was from the cycle 4. 42% (25/60) had dose reduction to 80mg due to AE, and that dose reduction was needed in 10% (6/60) at the first cycle. Grade 3-4 adverse events were observed in 55% (33/60). Conclusions: Starting dose of REG 120mg appears to have comparable efficacy to 160mg. Adverse events were generally consistent with the known safety profile of REG in this setting. Final results with additional follow-up on efficacy and safety outcome measures will be provided at the meeting. Clinical trial information: UMIN000018968.
A phase Ib/II study of cetuximab and pembrolizumab in RAS-wt mCRC.
Authors: Boland Patrick McKay , Hutson Alan , Maguire Orla , Minderman Hans , Fountzilas Christos , Iyer Renuka V. 
Published: January 2019

834 Background: Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody approved in RAS-wt metastatic colorectal cancer (mCRC). Pre-clinical data have suggested that cetuximab triggers immunogenic cell death and support an immunologic basis of activity. Small clinical data sets demonstrate that EGFR-based therapy preferentially increases TILs in colorectal hepatic metastases. This Phase Ib/II study was designed to assess the safety and clinical activity of cetuximab and pembrolizumab in metastatic colorectal cancer. Methods: Eligible pts were those with RAS-wt mCRC, ECOG performance status (PS) 0-2, with at least 1 prior line of therapy for advanced stage disease, and no prior treatment with an anti-EGFR antibody. The phase Ib study was designed as a safety lead-in with a de-escalation design. Pembrolizumab was administered at a fixed dose of 200 mg q3week with standard cetuximab dosing (400 mg/m2 loading dose, followed by 250 mg/m2 weekly). DLTs were defined as any ≥ grade 3 clinically significant toxicity which is possibly related and occurs within the first 6 weeks of therapy. For rash and hypomagnesemia only ≥ grade 4 toxicities were considered DLTs. Correlative serial biopsies were performed at baseline and at 9 weeks. Results: 9 patients, ages 33-73, were enrolled onto the Phase Ib study between 8/10/16 and 11/2/16. No DLTs were observed. The most common AEs of any cause observed were xerosis, dermatitis acneiform rash, hypomagnesemia, vomiting, and fatigue. ≥ Grade 3 toxicities were uncommon, but included hypomagnesemia (3), rash (1), urticaria (1), hypocalcemia (1), alk phos elevation (1), and ascites (1). 6/9 patients achieved stable disease lasting ≥ 16 weeks. Conclusions: The combination of cetuximab and pembrolizumab is well-tolerated in this study and can be administered at full dosages. Though hypomagnesemia appears prominent, no additional emergent AEs have been observed during or following the DLT period. The associated ongoing phase II study will enroll an additional 33 patients to assess the true efficacy of this regimen with dual primary endpoints of ORR and 6 month PFS. Clinical trial information: NCT02713373.
miR-30a-5p as a tumor suppressor gene in gastric cancer.
Authors: Min Jimin , Han Tae-su , Choi Boram , Hur Keun , Yanagihara Kazuyoshi , Kim V Narry , Lee Hyuk-Joon , Yang Han-Kwang 
Published: January 2019

84 Background: Gastric cancer (GC) is the second leading cause of cancer-related death. MicroRNAs (miRNAs) are an abundant class of negative gene regulator and regulate multiple gene targets. miRNAs control a wide range of biological functions such as cellular proliferation, differentiation and apoptosis. Moreover, many miRNAs are highly conserved, and their deregulation is often associated with human malignancies. The aims of this study are to determine the miR-30a functions as a tumor suppressor gene and to evaluate whether the miR-30a-5p is able to use the diagnostic or prognostic marker in GC. Methods: To identify the gastric tumor-associated miRNAs, miRNA microarray was performed using the gastric cancer tissues. qRT-PCR was employed to confirm the microarray results. Also, to determine the miR-30a-5p biological functions in GC, miR-30a-5p mimic or inhibitor was treated in GC cell lines. Results: In miRNA microarray data, miR-30a-5p was down-regulated in GC tissues compared to normal mucosa. When we performed qRT-PCR to confirm miR-30a-5p expression, it was frequently down-regulated in our GC cohort, (n = 30, P < 0.001). Furthermore, ectopic expression of miR-30a-5p decreased cell growth, migration capacity and colony formation in vitro. Conclusions: Taken together, the miR-30a-5p expression was frequently down-regulated in GC. In addition, the miR-30a-5p suppressed tumorigenesis. Therefore, we suggest that miR-30a-5p activation may be a useful strategy of GC patient therapy and it can serve as a diagnostic or prognostic marker for GC.
Phase II trial of oral S-1 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard chemotherapies (CCOG-1105 study).
Authors: Ezaka Kazuhiro , Nakayama Goro , Yokoyama Hiroyuki , Matsui Takanori , Umeda Shinichi , Sunagawa Yuki , Murotani Kenta , Ando Yuichi , Kodera Yasuhiro 
Published: January 2019

841 Background: The aim of this multicenter, single-arm phase II trial was to investigate the efficacy and safety of S-1 plus bevacizumab (BEV) as a salvage treatment for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies. Methods: Patients who had unresectable mCRC with mutant-type KRAS; were refractory to fluoropyrimidine, irinotecan, oxaliplatin; and had previous treatment with BEV were enrolled and received S-1 plus BEV therapy (bevacizumab 7.5 mg/kg on day 1 and S-1 40-60 mg bid on day 1-14, every 3 weeks). The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), tumor response, and safety. Results: A total of 27 patients were enrolled. After a median follow-up period of 12.3 months, the events of disease progression and death occurred in 26 patients (96%) and 20patients (74%), respectively. The median number of treatment cycles was 3 (range, 1-17 cycles). Median PFS was 2.3 months (95% confidence interval [CI], 2.2-2.4 months), and the median OS was 7.7 months (95% CI, 4.3-10.1 months). The overall response and disease control rates were 0% and 33%, respectively. The median tumor shrinkage rate (DpR) was -15% (range, -59 to 15%). The frequencies of hematological and non-hematological adverse events above grade three were 25% and 8%, respectively. Conclusions: S-1 plus BEV therapy could be feasible salvage line treatment for Japanese patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000006476.
A new look at the IDEA classification: Defining novel predictive and prognostic markers in stage III colon cancer.
Authors: Margalit Ofer , Mamtani Ronac , Yang Yu-Xiao , Reiss Kim Anna , Golan Talia , Halpern Naama , Aderka Dan , Giantonio Bruce J. , Shacham-Shmueli Einat , Boursi Shimon Ben 
Published: January 2019

845 Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for newly defined low- and high-risk stage III colon cancer patients, suggesting low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy vs doublet chemotherapy in low and high IDEA risk groups. Methods: Using the NCDB (2004-2014) we identified 56,728 and 47,557 individuals as low and high IDEA risk groups, respectively. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet vs monotherapy). In a secondary analysis, we examined the predictive value of subgroups of age. Results: Low and high IDEA risk groups derived similar benefit from doublet chemotherapy compared to monotherapy, with hazard ratios of 0.83 (95%CI 0.79-0.86) and 0.80 (95%CI 0.78-0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients above the age of 72 (HR = 0.95, 95%CI 0.90-1.01) and high-risk patients above the age of 85 (HR = 0.90, 95%CI 0.77-1.05). Conclusions: IDEA risk classification does not predict benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients above the age of 72.
Adenocarcinoma Ex goblet cell: A retrospective experience.
Authors: Das Satya , Berlin Jordan , Du Liping , Shi Chanjuan 
Published: January 2019

847 Background: Adenocarcinoma ex goblet cell tumors (AGCC) represent rare appendiceal neoplasms with neuroendocrine and adenocarcinoma features. They represent the most aggressive subset of goblet cell carcinoids (Group B and C) and are often categorized as chemotherapy unresponsive [Am J SurgPathol.2008;32(10):1429-43]. Despite this, most patients with AGCC are treated with colon cancer chemotherapy regimens. We explored outcomes in patients treated at our institution with these regimens. Methods: We performed a single center retrospective analysis of 22 biopsy-proven AGCC patients (13 men, 9 women, median age at diagnosis 54.5) at Vanderbilt who had undergone treatment for local or metastatic disease. PFS and OS were determined for each patient and stratified by features listed on Table 1. Patients who were lost to follow up were censored based on their last recorded clinic date. Results: 16 patients received chemotherapy in the metastatic setting and all 16 had peritoneal involvement; of these patients 4 underwent HIPEC. Median PFS and OS in HIPEC treated patients was 17 months and 33 months respectively. 8 patients received adjuvant chemotherapy with FOLFOX; 6 in the local setting and 2 in the metastatic setting. Patients with metastatic AGCC had a median PFS of 21.5 months and a median OS of 32.9 months. Patients with local disease had a median PFS of 32.8 months and an OS that was not reached (median duration of follow up 12.4 months). Conclusions: AGCC have a predilection for peritoneal spread. Patients who received either adjuvant FOLFOX post definitive surgery or FOLFOX/FOLFIRI in the metastatic setting post optimal cytoreduction had prolonged periods of PFS and OS. [Table: see text]
Relation between irinotecan-induced cholinergic syndrome and prognosis of colorectal cancer patients.
Authors: Fujii Hiroyuki , Hirata Taizo , Mura Takuya , Okada Yuko , Tashiro Hirotaka 
Published: January 2019

859 Background: It is well known that a cetuximab induced rash is strongly associated with improved survival of colorectal cancer patients. Irinotecan Induced Cholinergic Syndrome (IICS), manifesting in such events as early diarrhea and diaphoresis, is a notorious adverse effect of irinotecan. In this study, we reveal the relation between IICS and prognosis of colorectal cancer patients and examine the validity of IICS as a surrogate marker for the efficacy of irinotecan. Methods: We retrospectively reviewed data from 52 colorectal cancer patients who were treated with a chemotherapeutic regimen that included irinotecan at Kure Medical Center between 2012 and 2017. First, to assess the relation between adverse events and efficacy of irinotecan, patients who experienced IICS (n = 11) and did not experience IICS (n = 41) were analyzed from the aspect of overall survival (OS), progression-free survival (PFS), sex, age, dose, performance status (PS) and previous chemotherapy (PC). Kaplan-Meier survival curves were drawn for OS and PFS, and compared by means of a log-rank test. Secondly, to determine the response rate of butylscopolamine for IICS, we injected butylscopolamine 20mg into the irinotecan infusion bag and administered both agents through the intravenous line together to 11 patients who experienced IICS. Results: The presence of IICS was associated with a prolonged median OS (589 vs. 280 days, log-rank p = 0.0282; adjusted hazard ratio (HR) 0.27, 95% confidence interval [CI] 0.06-0.79, p = 0.0140), and prolonged median PFS (317 vs. 154 days, log-rank p = 0.1474; adjusted HR 0.56, 95% CI 0.22-1.25, p = 0.1635). There was no statistically significant difference between the two groups in terms of sex, age, dose, PS and PC. Ten patients of 11 patients who were administered butylscopolamine, experienced complete or partial improvement of IICS. The response rate was nearly 90%. Conclusions: The presence of IICS is associated with an improved OS for colorectal cancer patients and tends to have a positive correlation with PFS. IICS is a viable surrogate biomarker of the antitumor efficacy of irinotecan. As a prophylaxis of IICS, mixing butylscopolamine into the irinotecan infusion bag was remarkably effective.