bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in patients with initially resectable metastatic colorectal cancer: A GERCOR randomized phase III study (MIROX).
Authors: Hebbar Mohamed , Chibaudel Benoist , Andre Thierry , Mineur Laurent , Smith Denis , Louvet Christophe , Dutel Jean Luc , Ychou Marc , Legoux Jean-Louis , Mabro May , Auby Dominique , Brusquant David , Khalil Ahmed , Truant Stephanie , Hadengue Alexandra , Bonnetain Franck , Pruvot Francois-Rene , Dalban Cecile , De Gramont Aimery ,   GERCOR
Published: March 2020

3506 Background: Perioperative FOLFOX4 is the standard chemotherapy (CT) in patients with resectable metastases from colorectal cancer (CRC) (Nordlinger et al, Lancet 2008). To increase curability and reduce the risk of severe neuropathy, we evaluated the sequential administration of a dose-dense oxaliplatin-based regimen followed by an irinotecan-based regimen. Methods: Patients with CRC and initially resectable or resected metastases were randomized between arm A (control): FOLFOX4 (12 cycles; oxaliplatin 85 mg/m²) or arm B (investigational): FOLFOX7 (6 cycles; oxaliplatin 130 mg/m²) followed by FOLFIRI (6 cycles; irinotecan 180 mg/m²). CT was either perioperative or postoperative. Stratification criteria were: perioperative vs. postoperative CT, surgery alone vs. radiofrequency ablation +/- surgery, Blumgart’s prognostic score (0-1 vs. 2-3 vs. 4-5). Only one metastatic site was allowed, but the number of metastases per organ was not limited. The primary endpoint was disease-free survival (DFS). Results: From May 2004 to June 2010, 284 patients were randomized (142 in each arm). Baseline patient characteristics were similar in both arms. Liver was the main metastatic site. There was only one metastasis in 70 (49.3%) patients in arm A and 69 (48.6%) patients in arm B. CT was administered perioperatively in 168 (59.1%) patients, and postoperatively in 116 (40.9%) patients. In case of perioperative CT, R0-R1 resection was achieved in 58/85 (68.2%) patients in arm A and 67/83 (80.7%) patients in arm B. Grade 3 neuropathy occurred in 34 (23.9%) and 28 (20.0%) patients in arm A and B, respectively. Grade 3/4 thrombocytopenia and gastrointestinal toxicities (nausea, vomiting, diarrhea) were more frequent in arm B. Median follow-up was 50.4 months [95% CI: 45.6-54.4]. Median DFS were 22.4 months [95% CI: 17.9-36.2] in arm A and 23.0 months [95% CI: 19.7-35.6] in arm B (HR=0.97 [95% CI: 0.72-1.31]; p=.856). Conclusions: FOLFOX7 followed by FOLFIRI is not superior to the standard FOLFOX4 chemotherapy in patients with resectable metastatic colorectal cancer.
Impact on survival of primary tumor resection in patients with colorectal cancer and unresectable metastasis: Pooled analysis of individual patients’ data from four randomized trials.
Authors: Faron Matthieu , Bourredjem Abderrahmane , Pignon Jean-Pierre , Bouche Olivier , Douillard Jean-Yves , Adenis Antoine , Elias Dominique , Ducreux Michel 
Published: March 2020

3507 Background: In patients with colorectal cancer (CRC) and unresectable metastasis, the prognostic impact of primary tumor resection still remains a matter of debates. The goal of this study was to estimate, after adjustment for prognostic factors, the effect of primary tumor resection on survival. Methods: Individual patients’ data of the 1155 patients with metastatic CRC included in 4 first-line chemotherapy trials (FFCD 9601, FFCD 2000-05, ACCORD 13 and ML 16987) where retrieved. Patients were eligible for this study if they had synchronous metastasis judged unresectable. Primary endpoint was overall survival (OS), secondary endpoint was progression free survival (PFS). A Cox proportional hazard model stratified on the trial was used to estimate the impact on survival. Results: 810 patients beginning first-line chemotherapy with either fluoropyrimidine alone, oxaliplatin, irinotecan and/or bevacizumab were eligible. Patients with a history of resection (n = 478 (59%)), as compared to those without (n = 332 (41%)), were more likely to have colonic primary (p < 0.0001), lower carcino embryonic antigen (CEA) (p < 0.0001) or alkaline phosphatase (ALP) level (p=0.04) and normal white blood cell count (WBC) (p < 0.0001). In the univariate analysis, stratified on the trial, primary tumor resection was associated with a better OS (Hazard Ratio HR: 0.73 [0.63-0.84]; p < 0.0001) and PFS (HR : 0.73 [0.63-0.84]; p < 0.0001). Multivariate analysis, adjusted for primary tumor location, CEA, ALP and WBC levels, OMS performance status and number of metastatic sites confirmed that primary tumor resection was an independent predictor of better OS (HR : 0.63 [0.53-0.75] ; p < 0.0001), and PFS (HR : 0.82 [0.70-0.95] ; p = 0.0007). Significant interactions were found between resection and CEA level (p=0.02) and resection and primary tumor location (p=0.01) for OS (not for PFS) with a lower impact of resection with higher CEA levels or a colonic primary. Conclusions: This study confirmed the independent prognostic value on survival of primary tumor resection in patients with unresectable metastases of CRC.
BRAF, PIK3CA, and PTEN status and benefit from cetuximab (CET) in the treatment of advanced colorectal cancer (CRC): Results from NCIC CTG/AGITG CO.17.
Authors: Jonker Derek J. , Karapetis Christos Stelios , O'Callaghan Christopher J. , Marginean Celia , Zalcberg John Raymond , Simes John , Moore Malcolm J. , Tebbutt Niall Christopher , Price Timothy Jay , Daneshmand Manijeh , Hanson Jennifer , Shapiro Jeremy David , Pavlakis Nick , Gibbs Peter , Van Hazel Guy A. , Yu Min Lee Ursula Joan , Haq Rashida , Virk Shakeel , Tu Dongsheng , Lorimer Ian ,   NCIC Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group
Published: March 2020

3515 Background: CET, a monoclonal antibody targeting the epidermal growth factor receptor, improves overall survival (OS) and progression free survival (PFS) in patients (pts) with KRAS wild-type (WT) chemotherapy refractory CRC. BRAF and PIK3CA mutation status, and PTEN expression levels may further predict benefit from CET therapy. Methods: Available colorectal tumour samples were analyzed from a phase III trial of CET plus best supportive care (BSC) vs BSC alone (NEJM 2007; 357(20)). BRAF and PIK3CA mutations (MUT) identified in tumour-derived DNA using a high resolution melting analysis to identify amplicons with mutations were confirmed by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays constructed from available tumour blocks. For each biomarker, prognostic (treatment independent) effects were assessed in patients on the BSC alone arm. Predictive effects (benefit from CET) on OS and PFS among all patients and those in the KRAS wild-type subset were examined using a Cox model with tests for treatment-biomarker interaction, adjusting for covariates. Results: Of 401 pts assessed for BRAF status (70% of CO17 population), 13(3%) had mutations. Of 407 pts assessed for PIK3CA status (71% of CO17 population), 61(15%) had mutations. Of 205 pts assessed for PTEN (36% of CO17 population), 148(72%) were negative for IHC expression. No biomarker was prognostic for OS or PFS, and none were predictive of benefit from CET, either in the whole study population or the KRAS WT subset. Conclusions: In chemotherapy-refractory CRC, neither PIK3CA mutation status nor PTEN expression were predictive of benefit from CET therapy. BRAF mutations are uncommon in this setting. Larger sample sizes would be required to determine if BRAF status is predictive for CET benefit. [Table: see text]
Comparative evaluation of capecitabine or infusional leucovorin/5-fluorouracil (LV/5-FU) with or without oxaliplatin (Ox) for stage III colon cancer (CC): A pooled analysis of individual patient data from four randomized controlled trials.
Authors: Sun Weijing , Schmoll Hans-Joachim , O'Connell Michael , Cartwright Thomas H. , Twelves Christopher , McKenna Edward , Saif Wasif M. , Lee Luen F. , Yothers Greg , Haller Daniel G. 
Published: March 2020

3525 Background: A fluoropyrimidine + Ox is the standard of care for stage III CC but a fluoropyrimidine alone is recommended for selected patients in several practice guidelines. We assessed efficacy and safety of adjuvant capecitabine ± Ox vs. LV/5-FU ± Ox across a population of stage III CC patients enrolled in four trials. Methods: N = 5,819 patients from NSABP C-08, XELOXA, X-ACT, and AVANT were pooled and analyzed; bevacizumab-treated patients were excluded. Endpoints were disease-free survival (DFS, primary), relapse-free survival (RFS), overall survival (OS), and safety. Multivariate Cox regression analyses (MVA) controlled for age, gender, T, and N stage. Results: Patient demographics and disease characteristics (except lymph nodes examined) were well balanced across groups. The number of patients receiving capecitabine and LV/5-FU were 1,942 and 3,877, respectively. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). Five-year DFS was 62.8% for capecitabine ± Ox and LV/5-FU ± Ox. The capecitabine by Ox interaction was significant for OS with a trend for DFS and RFS; likely due to improved outcomes with capecitabine alone and similar outcomes for capecitabine or LV/5-FU + Ox. Serious adverse event (AE) rates were similar for LV/5-FU- and capecitabine-based therapy (16% vs. 20%, respectively). Overall, treatment-related grade 3/4 AEs were more common with LV/5-FU (59% vs. 47%). Treatment-related grade 3/4 AEs of interest included peripheral sensory neuropathy (5% vs. < 1%), diarrhea (12% vs. 15%), febrile neutropenia (2% vs. < 1%), and hand–foot syndrome (< 1% vs. 12%). Conclusions: Adjuvant capecitabine ± Ox and LV/5-FU ± Ox show comparableefficacy benefits for the treatment of stage III CC; further supporting capecitabine or LV/5-FU-based regimens as standard options for the adjuvant therapy of stage III CC. [Table: see text]
Analysis of PTEN in patients with advanced colorectal cancer (CRC) receiving capecitabine alone or in combination with bevacizumab with or without mitomycin C in the phase III AGITG MAX trial.
Authors: Price Timothy Jay , Hardingham Jenny , Lee Chee , Wrin Joe , Townsend Amanda Rose , Wilson Kate , Weickhardt Andrew James , Simes John , Murone Carmel , Tebbutt Niall Christopher 
Published: March 2020

3534 Background: There is an urgent need for potential biomarkers for anti-VEGF therapies. The tumour suppressor gene PTEN is thought to have a potential role as a biomarker for anti-EGFR therapy in CRC, but there is also evidence that decreased levels of PTEN leads to increased expression of VEGF suggesting a potential relationship to outcome with anti-VEGF therapy*. The prognostic value of PTEN also remains controversial. Methods: Patients enrolled in the Phase III MAX trial of capecitabine (C) +/- bevacizumab (B) (+/- mitomycin C (M)) with available tissue were analysed for PTEN expression (loss v no loss) as assessed using a Taqman copy number assay to measure copy number variation at the PTEN locus. PTEN status was correlated with progression-free survival (PFS) and overall survival (OS) outcomes. The predictive value of PTEN status for bevacizumab efficacy was also examined. Results: Of the original 471 patients enrolled in the trial, tissue from 302 (64.1%) patients were analysed. Baseline characteristics of those with and without tissue were comparable. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. Patients with PTEN loss were more likely to have rectal primary (p=0.01) and less likely to have lung metastasis (p=0.03). By using the comparison of C v CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS (Table). PTEN status is also not prognostic for PFS or OS in multivariate analyses adjusting for other baseline factors (Table). Conclusions: PTEN status did not significantly predict different benefit with anti-VEGF therapy. PTEN status was also not prognostic for survival in advanced colorectal cancer. [Table: see text]
Maintenance therapy with biweekly cetuximab (C) in the first-line treatment of metastatic colorectal cancer (mCRC): The NORDIC 7.5 study (NCT00660582), by the Nordic Colorectal Cancer Biomodulation Group.
Authors: Pfeiffer Per , Sorbye Halfdan , Qvortrup Camilla , Karlberg Mia , Naucler Gisela , Kersten Christian , Vistisen Kirsten , Lindh Birgitta , Glimelius Bengt 
Published: March 2020

3538 Background: NORDIC 7.5 is a multi-center phase II trial of Nordic FLOX plus biweekly C followed by maintenance C in first-line treatment of mCRC, KRASwild-type (KRASwt). The aim was to complement the data of the NORDIC VII trial, arm C (Tveit et al, ASCO GI 2011). Specifically, the goal was to substantiate efficacy and safety of biweekly C as maintenance therapy and to assess time to failure of strategy (TFS) as an end-point in maintenance therapy studies. Methods: Patients had KRASwt, measurable, non-resectable mCRC; no prior chemotherapy for metastases; WHO PS 0-2 and good organ function. Patients received 8 courses of FLOX (bolus 5FU/folinic acid days 1 + 2 with oxaliplatin day 1 every 2 weeks) plus biweekly C (500 mg/m2 every 2 weeks) for 16 weeks followed by biweekly C as maintenance therapy until progression (PD). After at least 2 months of maintenance therapy, patients restarted FLOX plus biweekly C at the time of RECIST PD, and continued until a second RECIST PD. The primary endpoint was response rate (RR). Eighty-six patients were planned to confirm a response rate of 60%. While awaiting the results of Nordic VII, we amended the protocol to include 150 patients. Secondary endpoints included PFS, OS, resection rate, and safety. TFS was an explorative endpoint. Results: From July 2008 to September 2010, 152 KRASwt patients were included in 11 Nordic centers. Results were updated December 2011. Median age 64 years; 94% PS 0-1. RR 62%, median PFS 8.0 months, median OS 23.2 months, median TFS 11.9 months. Ten patients (15%) had R0-resection of metastasis. FLOX + C was re-introduced in 47 of 85 patients (55%) who were candidates for re-treatment and was started median 18 days after PD. Median duration of re-introduction was 5 months (1-29), 9 patients (20%) had response. Elevated baseline platelets and neutrofiles were associated with poor OS. The most common grade 3/4 non-hematologic AEs in were diarrea (9%), skin rash (9%), infection without neutropenia (7%), and fatigue (7%) Conclusions: Maintenance therapy with biweekly cetuximab is an encouraging strategy with efficacy and toxicity comparable to weekly cetuximab.
Prospective study of EGFR intron 1 CA tandem repeats to predict factor benefit from cetuximab and irinotecan.
Authors: Antoniotti Carlotta , Loupakis Fotios , Cremolini Chiara , Zhang Wu , Yang Dongyun , Wakatsuki Takeru , Schirripa Marta , Salvatore Lisa , Ricci Vincenzo , Graziano Francesco , Masi Gianluca , Ruzzo Annamaria , Labonte Melissa Janae , Ning Yan , El-Khoueiry Rita , Falcone Alfredo , Lenz Heinz-Josef 
Published: March 2020

3540 Background: Retrospective experiences have investigated the potential influence of EGFR intron 1 CA repeats on the efficacy of cetuximab-containing treatments. Different series, adopting different criteria to define short (S) and long (L) variants, have provided contrasting results. Methods: We designed a prospective confirmatory study, to detect a HR for PFS of 1.75 for L- compared to SS genotypes in a population of KRAS and BRAF wild-type irinotecan-resistant mCRC pts treated with cetuximab and irinotecan. Estimating a prevalence of 60% of the SS variant and setting a two-sided alfa=0.05 with a power of 80%, 104 events were required. We defined S and L allelic variants those presenting < and ≥20 CA repeats, respectively. EGFR (CA)n repeat polymorphism was assessed following a 5’-end [γ-33P] ATP-labeled PCR protocol. Results: One-hundred-fifteen pts were included. At a median follow up of 21.9 months, PFS and OS were 5.2 and 13.4 months, respectively. Thirty-three (29%) out of 114 evaluable pts achieved response. EGFR (CA)n repeat genotype was L- and SS in 45 (40%) and 68 (60%) out of 113 evaluable cases. No differences in PFS or OS were observed between L- and SS genotypes (median PFS: 4.4 vs. 5.3 months, HR: 1.00 [95%CI: 0.67-1.51], p=0.991; median OS: 11.3 vs. 14.2 months, HR: 1.30 [95%CI: 0.80-2.22], p=0.261). Ten (22%) out of 45 L- pts achieved response compared to 22 (33%) out of 67 SS pts (Fisher’s Exact test: p=0.617). Other exploratory analyses adopting different cut-off values reported in literature led to similar results. Conclusions: This prospective study, including a clinically homogenous and molecularly selected population, does not confirm any predictive or prognostic effect for EGFR (CA)n repeat allelic variants with respect to the efficacy of cetuximab and irinotecan in advanced lines of treatment. The present experience strengthens the need of prospectively challenging retrospective findings, as an essential step on biomarkers’ way toward clinical practice.
Comparative effectiveness of sphincter-sparing surgery (SSS) versus abdomino-perineal resection (APR) in rectal cancer: Patient-reported outcomes (PROs) from NSABP R-04.
Authors: Ganz Patricia A. , Lopa Samia H. , Yothers Greg , Ko Clifford Y. , Arora Amit , Atkins James Norman , Bahary Nathan , Soori Gamini S. , Robertson John M. , Eakle Janice F. , Marchello Benjamin T. , Wozniak Timothy F. , Wolmark Norman ,   NSABP
Published: March 2020

3545 Background: R-04 is a trial of pre-surgical RT and either capecitabine or 5-FU with or without oxaliplatin in patients (Pts) with resectable rectal cancer. PROs were measured before treatment, post-RT, and 1 yr post-op. We compare PROs at 1 yr by type of surgery with hypothesis that APR Pts would have worse quality of life (QOL). Methods: Pts completed the FACT-C and EORTC-CR38 at all times. Baseline and 1 yr were compared within groups (SSS and APR) with paired t-test, and between groups at 1 yr, with adjustment for covariates of age, gender, clinical stage, baseline score, and surgery intent in a general linear model. These secondary/exploratory hypotheses were significant if p < 0.05. Results: 1,608Pts were randomized and 1405 completed baseline QOL form after consent, prior to treatment. 1,003 completed QOL form 1 yr post-op: 6 were ineligible, 10 did not have surgery, leaving 987 Pts. 615 had SSS and 372 had APR. 66.6% were male, 61.5% stage II, and almost all had post-surgical adjuvant chemotherapy. SSS Pts were significantly younger (60.3% vs. 53.5% < 59 yr, p=0.04). FACT-C total and subscale scores were not significantly different by surgery type at 1 yr, with only minimal decline from baseline in both groups. For SSS Pts, EORTC-CR38 scores significantly worsened for body image, sexual function, sexual enjoyment (all p <0.0001), while future perspective improved (p<0.0001) at 1 yr from baseline. All symptom subscales except weight loss and micturition showed worsened symptoms (GI tract, chemo side effects, defecation problems, sexual problems) all p < 0.0001 at 1 yr from baseline. Compared to APR Pts, SSS had less severe functional problems and symptoms, especially in sexual enjoyment, weight loss, GI symptoms, and body image, all significant. Conclusions: Contrary to prediction, there were no significant differences in FACT-C scores for SSS vs. APR. Symptoms and functional problems were detected by the EORTC-CR38, reflecting expected differences. The largest differences between the surgical treatments were for GI symptoms and body image. Information from these PROs may be useful in counseling Pts anticipating surgery for rectal cancer.
Phase Ib study of dulanermin combined with first-line FOLFOX plus bevacizumab (BV) in patients (Pts) with metastatic colorectal cancer (mCRC).
Authors: Kozloff Mark , Messersmith Wells A. , Kapp Amy V. , Ashkenazi Avi , Royer-Joo Stephanie , Portera Chia C. , Wainberg Zev A. 
Published: March 2020

3552 Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic pathways by binding to the pro-apoptotic death receptors DR4 and 5. This study assessed the safety of dulanermin combined with FOLFOX+BV as first-line therapy in mCRC pts. Methods: This was a multicenter, open-label dose-escalation and cohort expansion study with treatment until disease progression or treatment intolerance. Dulanermin was administered intravenously in 14-day cycles on Days 1, 2 and 3 at 4.5 mg/kg or 9 mg/kg, with FOLFOX, and BV 5 mg/kg on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 cycles (Days 1-28). Adverse events (AE) were recorded through all cycles. Response was assessed with RECIST (v1.0). Results: A total of 23 pts received 2-33 cycles (median 15) of dulanermin with FOLFOX+BV. No DLTs were reported. The most frequent AEs reported as dulanermin-related were fatigue (26%), neutropenia and nausea (22% each), and alanine aminotransferase increased and diarrhea (17% each). The most frequent Grade ≥3 AEs reported as dulanermin-related were neutropenia (13%) and infusion-related reaction (9%). Some of these events were reported as related to dulanermin and other study drugs. Three pts (13%) discontinued study treatment due to serious AEs: infusion-related reaction (2 pts, 9%; both reported as dulanermin-related) and pulmonary embolism (1 pt, 4%). Other reasons for discontinuation included disease progression (13 pts, 57%), physician’s decision and pt’s decision (2 pts each, 9%), and non-compliance (1 pt, 4%). Two pts are still receiving treatment. Among the 23 patients, best responses included 13 (57%) partial responses (9 confirmed and 4 unconfirmed), 7 (30%) stable disease and 3 (13%) progressive disease. Conclusions: Addition of dulanermin to first-line FOLFOX+BV was well tolerated overall in these mCRC pts. AEs were similar to those previously reported for FOLFOX+BV alone. Tumor responses suggest no adverse interactions between dulanermin and the standard first-line treatment evaluated in this study.
Prognostic impact of miR-146 polymorphism in patients with resected colorectal cancer.
Authors: Kim Jong Gwang , Chae Yee Soo , Lee Soo Jung , Kang Byung Woog , Moon Joon Ho , Sohn Sang Kyun , Choi Jun Young 
Published: March 2020

3554 Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. The rs2910164 is a C to G polymorphism located within the sequence of miR-164a precursor, which leads to a change from a C:U pair to a G:U mismatch in its stem region. Recent evidence suggested that the rs2910164 SNP in miR-146a was associated with development of familial breast and ovarian cancers, and prostatic cancer. The aim of this study was to investigate the association between this genetic variant and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 343 CRC patients underwent curative surgery were consecutively enrolled between 2004 and 2006. DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: With a median follow up of 42.3 months, the combined GG+CG genotype demonstrated a better survival outcome compared with the CC genotype in a Kaplan-Meier survival analysis. Multivariate analysis showed that the G allele of miR-146 was associated with better progression-free and disease-specific survival as a dominant model adjusted to age, sex, histologic grade and stage [HR=0.54 and 0.49; p = 0.018 and 0.025, respectively]. Moreover, the tumors containing the G allele were histologically associated with more prominent lymphovascular invasion. Conclusions: Our results suggest that miR-146 polymorphism is possible prognostic marker in operated CRC patients in Korean.