bluuebunny/crossref_metadata_2025_split huggingface dataset:
The skin types closely related to development of the facial acneiform rash and the therapeutic effects of EGFR inhibitors in RAS wild-type metastatic colorectal cancer: Ancillary analysis of FAEISS study.
Authors: Yoshikawa Syusuke , Yamazaki Naoya , Kiyohara Yoshio , Nozawa Keiko , Fukuda Haruhiko , Shibata Taro , Hasegawa Akiko , Takahashi Masanobu , Masuishi Toshiki , Kawazoe Akihito , Hamaguchi Tetsuya , Tsushima Takahiro , Machida Ryunosuke , Kikuchi Katsuko , Nakai Yasuo , Takatsuka Sumiko , Nisina Tomohiro , Mizutani Hitoshi , Takashima Atsuo 
Published: May 2020

3637 Background: At ESMO2019, we reported the primary results of a randomized controlled trial (FAEISS study) investigating the efficacy of topical corticosteroid treatment to facial acneiform rash (AR) by EGFR inhibitors comparing groups starting with a very strong topical corticosteroid and the standard weak topical corticosteroid. As an ancillary analysis, we investigated the association between AR and the pre-treatment skin types, as well as between the skin types and therapeutic effects of EGFR inhibitors on the primary disease. Methods: Utilizing pre-treatment clinical photos of the face taken according to the method determined by FAEISS study protocol, we divided the skin types into categories including enlarged pore, oiliness, xerosis, wrinkles, skin color/redness, and allocated the score (1-3) by central review. The severity of AR occurred during the study was graded and was evaluated the association with the specific skin type by Fisher’s exact test. We also investigated the association between the skin types and the best overall response (RECISTv1.1) to EGFR inhibitor therapy on the primary disease using the Cochran-Armitage trend test. Results: Of the registered 172 cases of RAS wild-type metastatic colorectal cancer [104 men and 68 women, median age = 68 (26-79)], omitting the cases with unevaluable data, finally we analyzed 146 cases for associations between the skin types and AR and 147 cases for best overall response. Interestingly, AR developed 13.6% of enlarged pore score 1, 29% of score 2 and 45.8% of score 3, and patients with enlarged pore tended to have more AR (p = 0.058). Surprisingly, the response(CR/PR/SD) of the primary disease were 59.1% of the enlarged pore score 1, 70.6% of score 2 and 87.0% of score 3, and showed statistically significant trend(p < 0.038). Conclusions: This study suggested that a skin type (enlarged pore) is a possible marker predicting AR risk in EGFR inhibitor therapy for RAS wild-type metastatic colorectal cancer, and better therapeutic effects of EGFR inhibitors.
First-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS-BRAF wild-type metastatic colorectal cancer elderly patients: The PANDA study.
Authors: Lonardi Sara , Schirripa Marta , Buggin Federica , Antonuzzo Lorenzo , Merelli Barbara , Boscolo Giorgia , Cinieri Saverio , Di Donato Samantha , Lobefaro Riccardo , Moretto Roberto , Formica Vincenzo , Passardi Alessandro , Ricci Vincenzo , Pella Nicoletta , Scartozzi Mario , Zustovich Fable , Zagonel Vittorina , Fassan Matteo , Boni Luca , Loupakis Fotios ,   Gono Group
Published: May 2020

4002 Background: Data on first-line treatment efficacy in elderly patients are limited. Many analyses adopt a questionable cut-off of 65 years and specific evidence with anti-EGFRs is low. FOLFOX-panitumumab (pan) is an option for RAS wild-type (wt) untreated mCRC patients. Guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, but no randomized studies have ever explored the role of the combination with an anti-EGFR. Methods: This is a prospective, open-label, multicenter phase II randomized trial. Unresectable and previously untreated RAS- BRAF wt mCRC patients aged ≥70 were randomized to receive FOLFOX-pan (arm A), or 5FU/LV-pan (arm B) for up to 12 cycles followed by pan maintenance until PD. The primary EP was PFS in both arms. Stratification criteria were age (≤75 vs > 75 years), ECOG PS (0–1 vs 2) and geriatric assessment with G8 Score (≤14 vs > 14). In each treatment arm, the null hypothesis for median PFS was set at ≤6 months. Assuming an expected median PFS time ≥9.5 months with both experimental regimens, a sample size of 90 patients in each arm granted to the study a power of 90%, with a type I error rate equal to 5% (1-sided Brookmeyer-Crowley test) for rejecting the null hypothesis. No formal comparison between the two arms was planned. Results: From Jul 2016 to Apr 2019 a total of 394 patients were screened, 211 were deemed eligible for inclusion and 185 were randomized (92 arm A and 93 arm B). Main pts’ characteristics were (arm A/B): males 66%/61%; median age 77/77y; PS≥1 49%/55%; right colon 23%/21%; G8 > 14 31%/30%. At a median follow up of 20.5 mos, 135 (arm A/B: 64/71) PD events were collected. Median PFS was 9.6 (95% CI 8.8-10.9) in arm A with FOLFOX-pan and 9.1 (95% CI 7.7-9.9) in arm B with 5FU/LV-pan. Response rates were (arm A/B): 65%/57%. Grade 3-4 toxicities were (arm A/B): neutropenia 9.8%/1.1%; diarrhea 16.3%/1.1%; stomatitis 9.8%/4.4%; neurotoxicity 3.3%/0%; fatigue 6.5%/4.4%; skin rash 25%/24.2%, hypomagnesemia 3.3%/7.7%. Conclusions: Large prospective randomized studies in molecularly selected elderly mCRC are feasible with multicenter collaborative efforts. Primary EP was met in both treatment arms. 5FU/LV plus panitumumab for up to 12 cycles followed by panitumumab maintenance until PD might be a reasonable option in elderly mCRC patients with RAS/BRAF wt tumors deserving further investigations in phase III trials. Clinical trial information: NCT02904031 .
Celecoxib in addition to standard adjuvant therapy with 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) in stage III colon cancer: Results from CALGB/SWOG 80702.
Authors: Meyerhardt Jeffrey A. , Shi Qian , Fuchs Charles S. , Niedzwiecki Donna , Zemla Tyler J. , Kumthekar Priya , Guthrie Katherine A , Couture Felix , Kuebler J. Phillip , Bendell Johanna C. , Kumar Pankaj , Lewis DeQuincy Andrew , Tan Benjamin R. , Bertagnolli Monica M. , Grothey Axel , Hochster Howard S. , Goldberg Richard M. , Venook Alan P. , Blanke Charles David , Shields Anthony Frank 
Published: May 2020

4003 Background: Aspirin and cyclooxygenase-2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. CALGB/SWOG 80702 tested the effect of celecoxib, a COX-2 inhibitor, on reducing the risk of recurrence in stage III CC. Methods: CALGB/SWOG 80702 is a 2x2 randomized controlled phase III trial of 3 v 6 months of adjuvant FOLFOX (data previously reported as part of the IDEA collaboration) with concurrent celecoxib (400 mg daily) v placebo x 3 yrs for patients (pts) with resected stage III CC. The primary endpoint of the trial is disease-free survival (DFS), defined as time from randomization to recurrence or death from any cause. The trial was designed to provide 91% power to detect a hazard ratio (HR) of 0.79 in favor of celecoxib with 2-sided alpha = 0.05 (775 events required); due to slowing accumulation of events 4 years after complete accrual, power was lowered to 85% with same HR and alpha assumptions (696 events required). The DSMB released data on February 24, 2020 at median f/u of 5.6 yrs with 689 DFS events. Results: Between June 2010 and November 2015, 2,526 pts were consented and randomized to the trial. Treatment arms were well balanced by patient and tumor prognostic features, as well as low-dose aspirin use. Baseline characteristics included 45% female, 18% non-White, 8% Hispanic, 15% T4, 26% N2. 3-yr DFS for celecoxib was 76.3% v 73.3% for placebo (HR 0.89 [95% CI 0.77-1.04]; P = 0.14). 5-yr overall survival (OS) was 83.9% for celecoxib v 81.7% for placebo (HR 0.87 [95% CI 0.72-1.05]; P = 0.14). When considering the 4 treatment arms separately, 3-yr DFS was 77.0% for 12 months FOLFOX + celecoxib, 74.9% for 12 months FOLFOX + placebo, 75.5% for 6 months FOLFOX + celecoxib, and 71.9% for 6 months FOLFOX + placebo (log rank P = 0.22; P interaction = 0.64). There were no significant differences in grade 3-4 toxicity with celecoxib v placebo. Compliance with protocol celecoxib treatment, defined as 3 yrs of therapy completion or recurrence/death while on treatment, was 58.1% pts on celecoxib and 60.2% pts on placebo. Conclusions: The addition of celecoxib to standard chemotherapy did not significantly improve DFS or OS. Clinical trial information: NCT01150045 .
A randomized phase II/III trial comparing hepatectomy followed by mFOLFOX6 with hepatectomy alone for liver metastasis from colorectal cancer: JCOG0603 study.
Authors: Kanemitsu Yukihide , Shimizu Yasuhiro , Mizusawa Junki , Inaba Yoshitaka , Hamaguchi Tetsuya , Shida Dai , Ohue Masayuki , Komori Koji , Shiomi Akio , Shiozawa Manabu , Watanabe Jun , Suto Takeshi , Kinugasa Yusuke , Takii Yasumasa , Bando Hiroyuki , Kobatake Takaya , Kato Tomoyuki , Shimada Yasuhiro , Katayama Hiroshi , Fukuda Haruhiko 
Published: May 2020

4005 Background: The role of adjuvant chemotherapy after hepatectomy is controversial for liver only metastases from colorectal cancer (LM). Current recommendations for oxaliplatin-containing adjuvant regimen (FOLFOX) for LM are based on extrapolation of the results of the EORTC intergroup trial 40983, which showed that perioperative FOLFOX confirmed a progression-free survival benefit but did not affect overall survival (OS) in LM patients. We conducted a randomized controlled trial to determine if adjuvant modified FOLFOX (mFOLFOX) is superior to hepatectomy alone for LM. Methods: Eligible patients aged 20-75 years who had histologically proven colorectal adenocarcinoma with an unlimited number of LM were randomly assigned (1:1) to receive either adjuvant mFOLFOX6 (oxaliplatin 85mg/m2, l-LV 200 mg/m2, 5-FU bolus 400 mg/m2 and 2400mg/m2 over 48 h), for 12 cycles after surgery (CTX arm), or surgery alone (S alone arm). When treatment compliance after 9 courses of CTX was as high as expected in phase II, the registration was continued in phase III. The primary endpoint of phase III was disease-free survival (DFS), and the secondary endpoints were OS, toxicity, and sites of relapse. The planned sample size was 150 patients (pts) per arm, with a one-sided alpha of 5%, and 80% power detecting a 5y-DFS difference of 12% (25% with S alone vs. 37% with CTX). Results: Between Mar. 2007 and Jan. 2019, 300 patients were randomized. 151 pts were allocated to CTX, and 149 pts to S alone. When the third interim analysis of phase III was performed in Dec. 2019, the DSMC recommended the early termination of the trial because a statistically significant difference in terms of DFS but the futility in terms of OS was found. With a median follow-up period of 54 months for disease-free surviving patients, the 3y-DFS was 52.1% (95% CI 43.2 – 60.2) with CTX and 41.5% (33.2 – 49.6) with S alone (hazard ratio 0.63 [0.45 – 0.89], one-sided p = 0.002 < 0.0163 for the one-sided alpha level at the interim analysis). However, the 3y-OS was 86.6% (79.2-91.4) with CTX and 92.2% (86.0 – 95.8) with S alone (hazard ratio 1.35 [0.84 – 2.19]). The 5y-OS was 69.5% (59.6-77.5) with CTX and 83.0% (74.5-88.9) with S alone. Median OS after recurrence was 38.4 months in the CTX arm and 87.6 in the S alone arm. Conclusions: DFS did not correlate with OS for LM. Postoperative chemotherapy with mFOLFOX6 improves DFS but worsens OS over surgery alone due to more deaths after recurrence in the CTX arm. Adjuvant mFOLFOX is not beneficial to patients after hepatectomy for LM. Clinical trial information: UMIN000000653 .
Circulating tumor DNA to detect minimal residual disease, response to adjuvant therapy, and identify patients at high risk of recurrence in patients with stage I-III CRC.
Authors: Tarazona Noelia , Henriksen Tenna V , Carbonell-Asins Juan Antonio , Reinert Thomas , Sharma Shruti , Roda Desamparados , Shchegrova Svetlana , Huerta Marisol , Roselló Susana , Renner Derrick , Sethi Himanshu , Zimmermann Bernhard , Aleshin Alexey , Cervantes Andres , Andersen Claus Lindbjerg 
Published: May 2020

4009 Background: The clinical utility of tracking circulating tumor DNA (ctDNA) as a non-invasive biomarker for detecting minimal residual disease (MRD) and stratifying patients based on their risk of developing relapse has been well established in colorectal cancer (CRC). This study evaluates the detection and longitudinal monitoring of ctDNA in CRC patients pre- and post-operatively, during and after adjuvant chemotherapy (ACT). Methods: The prospective, multicenter cohort study recruited patients (n = 193) diagnosed with resected stage I-III CRC. Plasma samples (n = 1052) were collected at various timepoints with a median follow up of 21.6 months (4.6-38.5 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic mutations identified. Multiplex PCR assays were designed to 16 tumor-specific single-nucleotide variants to track ctDNA in plasma samples. The study evaluated the relationship between ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by ctDNA status postoperatively and post-ACT. Multivariable analysis was performed with all clinical variables. Best model was selected according to Akaike Information Criterion. Results: Pre-operatively ctDNA was detected in 90% (n = 166/185) of the patients. Post-operative ctDNA status prior to ACT was assessed in 152 patients, of which 9.2% (14/152) were identified to be MRD-positive and 78.5% (11/14) eventually relapsed. In contrast, 10.1% (14/138) of MRD-negative cases relapsed (HR: 16.53; 95% CI: 7.19-38.02; p < 0.001). Longitudinal ctDNA-positive status, post-ACT (n = 84) and post definitive therapy (n = 139) was associated with a 27.92 HR (95% CI: 9.16-85.11; p < 0.001) and a 47.52 HR (95% CI: 17.34-130.3.; p < 0.001), respectively. In the multivariable analysis, longitudinal ctDNA status was the only significant prognostic factor associated with RFS (HR: 53.19, 95% CI: 18.87-149.90; p < 0.001). Serial ctDNA analysis detected MRD up to a median of 9.08 months (0.56-16.5 months) ahead of radiologic relapse with a sensitivity of 79.1% and specificity of 99%. Conclusions: Postoperative ctDNA analyses detect patients with high-risk of recurrence, with near 100% specificity. Early detection of MRD and longitudinal monitoring of ctDNA could guide treatment decisions. Intervention trials to assess the clinical benefit of ctDNA use are underway.
FOLFOXIRI/bevacizumab (bev) versus doublets/bev as initial therapy of unresectable metastatic colorectal cancer (mCRC): A meta-analysis of individual patient data (IPD) from five randomized trials.
Authors: Cremolini Chiara , Antoniotti Carlotta , Stein Alexander , Bendell Johanna C. , Gruenberger Thomas , Masi Gianluca , Ongaro Elena , Hurwitz Herbert , Falcone Alfredo , Schmoll Hans-Joachim , Di Maio Massimo 
Published: May 2020

4015 Background: Several randomized trials demonstrated that intensifying the upfront chemotherapy in combination with bev is beneficial for mCRC patients with an increased incidence of some adverse events. All trials had primary endpoints other than OS, and a proper estimation of the magnitude of the OS benefit from FOLFOXIRI/bev versus doublets (FOLFIRI or FOLFOX)/bev is currently lacking. Within each trial, subgroup analyses failed to identify predictors of benefit from the intensified therapy. To test OS with higher power compared to single trials, and to explore interaction of treatment effect with main patients’ and disease characteristics, we performed an IPD meta-analysis. Methods: IPD were collected from 5 randomized trials: CHARTA (NCT01321957), OLIVIA (NCT00778102), STEAM (NCT01765582, only combined FOLFOXIRI/bev and FOLFOX/bev arms), TRIBE (NCT00719797) and TRIBE2 (NCT02339116). Primary endpoint was OS. Secondary endpoints included PFS, objective response rate (ORR), R0 resection rate, G3/4 adverse events, and subgroup analyses. All statistical analyses were by intention-to-treat, stratified by trial. Results: 1697 pts randomized to FOLFOXIRI/bev (N=846) or doublets/bev (N=851) were included. Among pts in the doublets/bev group, 595 (70%) received FOLFOX/bev and 256 (30%) FOLFIRI/bev. At a median follow up of 39.9 mos, pts assigned to FOLFOXIRI/bev reported significantly longer OS than those assigned to doublets/bev (median OS 28.9 vs 24.5 months; HR 0.81 [95%CI 0.72-0.91], p<0.001), with no significant heterogeneity among trials (p=0.39; I2=2%). The estimated 5-yr OS was 22.3% vs 10.7% (p<0.001). No significant interaction effect between treatment arm and OS was demonstrated in terms of metastatic spread (liver-limited vs. not liver-limited p=0.665), primary side (p=0.656), and RAS/BRAF status (p=0.337). Pts assigned to FOLFOXIRI/bev achieved longer PFS (median PFS 12.2 vs 9.9 months; HR 0.74 [95%CI 0.67-0.82], p<0.001), higher ORR (64.5% vs 53.6%, p<0.001), higher R0 resection rate (16.4% vs 11.8%, p=0.007), and experienced higher rates of G3/4 neutropenia (p<0.001), febrile neutropenia (p=0.019), mucositis (p=0.024), nausea (p=0.016), and diarrhea (p<0.001). Conclusions: FOLFOXIRI/bev determines a clinically and statistically significant improvement of mCRC patients’ OS vs doublets/bev with a meaningful effect also on 5-yr OS, PFS, ORR and R0 resection rate. No significant heterogeneity among explored subgroups was found.
First-line biological agents plus chemotherapy in elderly patients with metastatic colorectal cancer: A retrospective pooled analysis.
Authors: Garcia-Alfonso Pilar , Diaz-Rubio Eduardo , Abad Albert , Carrato Alfredo , Massuti Bartomeu , Rodríguez Alonso Rosa , Manzano Jose Luis , Muñoz Martín Andres J. , Durán Gema , García de Paredes Beatriz , Safont Aguilera Maria Jose , Ferreiro Monteagudo Reyes , Martinez de Castro Eva , González Flores Encarnación , Valladares-Ayerbes Manuel , Gravalos Castro Cristina , Alonso Orduña Vicente , Vieitez Jose María , Escudero Pilar , Aranda Enrique 
Published: May 2020

4017 Background: Biological agents, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding appropriate management of elderly patients with mCRC is lacking. This study compared the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. Methods: This retrospective analysis used pooled data from five Spanish TTD collaborative group studies of adults with advanced CRC who received first-line treatment with bevacizumab, cetuximab or panitumumab, stratified by age (≥65 vs < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. Results: In total, 999 patients from five studies were included in the analysis; 480 (48%) were aged ≥65 years and 519 (52%) were aged < 65 years; 733 (73.37%) were treated with bevacizumab, 189 (18.92%) received cetuximab and 77 (7.71%) received panitumumab. Median PFS did not significantly differ between patients aged ≥65 versus < 65 years (9.9 vs 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88–1.17). Median OS was significantly shorter in older versus younger patients (21.3 vs 25.0 months; HR 1.21; 95% CI 1.04–1.41; P = 0.0132). There was no significant difference between older versus younger patients in ORR (59% vs 62%). Older patients experienced more treatment-related grade ≥3 adverse events. Conclusions: Biological agents are an effective first-line treatment option for elderly patients with mCRC, with comparable efficacy in PFS and ORR to that observed in younger patients and a manageable safety profile.
CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer.
Authors: Fakih Marwan , Desai Jayesh , Kuboki Yasutoshi , Strickler John H. , Price Timothy Jay , Durm Greg Andrew , Falchook Gerald Steven , Denlinger Crystal S. , Krauss John C. , Shapiro Geoffrey , Kim Tae Won , Park Keunchil , Coveler Andrew L. , Munster Pamela N. , Li Bob T. , Kim June , Henary Haby Adel , Ngarmchamnanrith Gataree , Hong David S. 
Published: May 2020

4018 Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation is associated with poor prognosis in colorectal cancer (CRC). AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C by locking it in the inactive guanosine diphosphate-bound state. In a previous interim analysis of the phase 1, first-in-human trial of AMG 510, we observed a favorable safety profile and preliminary antitumor activity in patients (pts) with advanced solid tumors harboring KRAS p.G12C. Here, we present updated data in pts with CRC. Methods: Key inclusion criteria were KRAS p.G12C mutation identified through molecular testing, measurable disease, and progression on standard therapy. Primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), as assessed per RECIST 1.1, and overall survival (OS). Oral daily doses of 180, 360, 720, and 960mg were tested in the dose escalation phase, and 960mg dose was selected for the expansion phase. Results: As of Jan 8, 2020, 42 pts with CRC (21 female [50%], median age: 57.5 years [range: 33–82]) were enrolled and dosed (25 on 960mg). All pts received prior systemic therapies; 19 pts (45.2%) received > 3 prior lines. Median follow-up was 7.9 months (mos) (range: 4.2–15.9). 13 pts (31.0%) died, and 8 pts (19.0%) remained on treatment (tx). 22 (52.4%) and 8 (19.0%) pts had remained on tx for more than 3 and 6 months, respectively. Progressive disease was the most common reason for tx discontinuation. 20 pts (47.6%) had tx-related adverse events (TRAEs): 18 (42.9%) had grade 2 or lower TRAEs; 2 (4.8%) had grade 3 TRAEs, which were diarrhea (2.4%) and anemia (2.4%). There were no dose-limiting toxicities, fatal TRAEs, or TRAEs leading to tx discontinuation. Overall, ORR and DCR were 7.1% (3/42) and 76.2% (32/42), respectively. At 960mg, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 3 pts with PR had duration of response of 1.5, 4.2, and 4.3 months, respectively, and their responses were still ongoing at data cutoff. In all pts treated with all doses, median duration of stable disease was 4.2 mos (range: 2.5[+]–11.0). PFS/OS will be reported. Conclusions: In pts with heavily pretreated KRAS p.G12C mutant CRC, AMG 510 monotherapy was well tolerated, with the majority of pts achieving disease control. Study is ongoing. Clinical trial information: NCT03600883 .