bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: A randomized phase II study (The ADORE).
Authors: Hong Yong Sang , Nam Byung-Ho , Jung Kyung Hae , Lee Jae-Lyun , Kim Kyu-Pyo , Park Young Suk , Park Joon Oh , Kim Sun Young , Kim Tae-You , Kim Jee Hyun , Ahn Joong Bae , Kim Tae Won 
Published: March 2020

3570 Background: Preoperative chemoradiotherapy (Pre-CRT) with fluoropyrimidines (Fp) followed by surgery is one of the standard treatments for patients (pts) with locally advanced rectal cancer (LARC); however, the role of adjuvant chemotherapy is still controversial. The aim of this study is to investigate the efficacy of adjuvant FOLFOX for LARC pts who underwent Fp-based Pre-CRT and complete total mesorectal excision (TME). Methods: This randomised phase II study accrued LARC pts whose ypStage was II (ypT3-4/ypN0) or III (any ypT/ypN1-2) after Fp-based Pre-CRT followed by TME. Pts were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-FU 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 on D1, 5-FU bolus 400 mg/m2 on D1, 5-FU infusion 2400 mg/m2 for 46 hours q 2 weeks X 8 cycles). The primary endpoint was disease-free survival (DFS). Results: A total of 320 pts were randomly assigned (161 FL and 159 FOLFOX) between November 2008 and June 2012, the arms were balanced. By intent-to-treat analysis, estimated 2-year DFS rate was 82.0% in FOLFOX arm and 69.4% in FL arm (HR 0.46 [95% CI, 0.28-0.76], p=0.002) after the median follow-up duration of 22.5 months. The statistical improvements of DFS were maintained regardless of ypStage: 2-year DFS rate was 89.7% (FOLFOX) vs 76.4% (FL) in pts (n=122) with ypStage II (HR 0.32 [0.10-0.98], p=0.035), and 78.1% (FOLFOX) vs 64.4% (FL) in pts (n=198) with ypStage III (HR 0.49, [0.27-0.86], p=0.011). All grade leucopenia (32% vs 22%), neutropenia (70% vs 46%), thrombocytopenia (26% vs 2%) and sensory neuropathy (71% vs5%) were more frequently observed in FOLFOX arm; however, grade 3/4 adverse events (AE) were not different between arms. Conclusions: Adjuvant FOLFOX improved 2-year DFS relative to FL for LARC pts whose ypStage II or III after Fp-based Pre-CRT followed by TME. Significant AEs were not different between arms. The DFS results will be updated in the presentation. Clinical trial information: NCT00807911.
Survival benefit and complications of primary tumor resection (PTR) in patients with stage IV colorectal cancer (CRC) in the era of modern chemotherapy: A systematic review and meta-analysis.
Authors: Ahmed Shahid , Shahid Rabia K , Pahwa Punam , Kanthan Selliah , Reeder Bruce , Yadav Sunil , Sami Amer , Haider Kamal , Leis Anne 
Published: March 2020

3580 Background: Although there is evidences that PTR in advanced CRC may improve outcome, most studies were conducted during the period of monotherapy with 5-fluorouracil. Limited data is available regarding potential benefits and risk of PTR in patients with stage IV CRC treated with modern chemotherapy (MC). A recent phase II study suggested that outcomes are not compromised by leaving the primary colon tumor intact in such patients (JCO.2012;30:3223). Purpose:To compare survival of patients with advanced CRC who underwent PTR with patients without resection in the era of MC. The review also aims to determine post-operative mortality and non-fatal complications rates, primary tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR) and quality of life (QOL). Methods: A literature search was conducted by using CENTRAL (2012), Medline (1946-2012), and EMBASE (1947-2012). Studies involving patients with stage IV CRC who underwent PTR were selected with restriction to publication dates from 2000, English language and human studies. Screening, evaluation of relevant articles and data abstraction was done in duplication and agreement was assessed. Articles that met the inclusion criteria were assessed for quality by using Ottawa-Newcastle score. Data was collected and synthesized as per protocol. Results: Of total of 3,379 reports, 10 retrospective studies were selected with patients population of 2,655. Among 2,655 patients, 1616 (61%) underwent PTR with a median overall survival of 18.7 months (range: 11-30.7) compared with 12.9 months (range: 5.8-22) in the control. The HR for survival was in 0.68 (95% CI: 0.56-0.83) favoring the PTR. Mean 30 days post-operative mortality rate in the PTR group was 3.9% (95% CI: 0-11). Mean PTCR and NSPR in the control group were 27.4% (95% CI: 16.4-38.5) and 27% (95% CI: 12.5-41.6) respectively. No study provided QOL. Conclusions: The retrospective data favors PTR in advanced CRC in the era of modern chemotherapy. Future prospective randomized trials are warranted to confirm the findings.
The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC).
Authors: Hochster Howard S. , Messersmith Wells A. , O'Neil Bert H. , Groshen Susan G. , Lenz Heinz-Josef , Cohen Deirdre Jill , Denlinger Crystal Shereen , Gold Philip Jordan , Eckhardt S. Gail , Locker Gershon Y. , Ames Patricia , McKinley Marti , Leichman Lawrence P. ,   Academic GI Cancer Consortium (AGICC)
Published: March 2020

3587 Background: There are few therapies for second-line KRASm CRC. Inhibiting downstream signal transduction may offer therapeutic options. Use of selumetinib (MEK 1/2 inhibitor; AstraZeneca) is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI + SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin + bevacizumab regimen; PS 0-1; acceptable organ function. Patients (Pts) were treated with IRI 180 mg/m2 iv q2w and SEL 50 or 75 mg po bid. Dose escalation was traditional 3+3 (50 mg bid SEL, then 75 mg bid). In Part B/phase II, primary endpoint was PI-determined response rate (RR) by RECIST. A Simon 2-stage design allowed expansion to 45 pts if ≥1 responses in 20 pts was seen; ≥4/45 responses would be encouraging, when compared to historical RR of 4% (and median PFS 2.5 mo) [EPIC, Sobrero 2008], with approximately 90% power to detect an ORR of 15% at the 10% alpha level (one-sided). Results: N =32 pts entered; 31 treated. Median age was 54 (27-75) yrs; 18 male and 24 Caucasian. The first 3 pts tolerated SEL 50 mg bid without DLT and the remaining 28 were treated at 75 bid. Median number of cycles on study was 3.5 and median PFS was 3.4 mo. Grade 3 AEs included (N): diarrhea 3, fatigue 2, neutropenia 2, and 1 each thrombocytopenia, enteritis, GI bleed, rash. There was one Grade 4 neutropenia. The best PI-reported response included 3 (10%) confirmed PR and 16 (52%) SD [including 1 unconfirmed PR]. 6 patients were on study for more than 6 (up to 22) months. The study was terminated early due to non-protocol considerations. Conclusions: In this small study, the RR of 10% and med PFS of 3.4 mo in pts with KRASm CRC treated with IRI + SEL in 2nd line are promising compared with prior studies in non-selected patients. MEK inhibition in KRASm CRC should be explored further. Supported in part by AstraZeneca.
Prognostic stratification of k-RAS wild type colorectal cancer patients receiving irinotecan-cetuximab treatment: Preliminary results of a prospective study.
Authors: Scartozzi Mario , Giampieri Riccardo , Mandolesi Alessandra , Abouelkhair Khaled Mahmoud , Loretelli Cristian , Del Prete Michela , Faloppi Luca , Bittoni Alessandro , Bianconi Maristella , Cecchini Luca , Ibrahim Ezzeldin M. , Bearzi Italo , Cascinu Stefano 
Published: March 2020

3591 Background: Translational research identified numerous putative markers for a “beyond-k-RAS” selection of colorectal cancer patients receiving cetuximab, but none of these entered clinical practice mainly because prospective validation is lacking. The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed may be able to predict patients’ clinical outcome more accurately than k-RAS status alone. Methods: Metastatic, K-RAS wild type colorectal cancer patients, candidate to receive second/third-line cetuximab with chemotherapy have been prospectively allocated, after informed consent, into 2 groups on the basis of their genetic profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) and unfavourable (any of the previous markers altered or mutated). All patients received cetuximab treatment as planned by treating physician who was unaware of biomarkers results. To detect a difference in terms of response rate (RR) among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%), assuming a probability alpha of 0.05 and beta of 0.05, required sample size will be 46 patients. Results: 31 patients have been enrolled, most patients (27, 86%) received cetuximab as third-line. Eleven patients (35%) were allocated to the favourable profile and 20 patients (75%) to the unfavourable profile. Patients with the unfavourable profile showed 1 BRAF mutation, 2 PIK3CA exon 20 mutations, 12 cases of EGFR GCN < 2.6, 13 cases of HER-3 and 11 cases of IGF-1 overexpression respectively. RR in the favourable and unfavourable group was 7/11 (64%) and 1/20 (5%) (p= 0.008) respectively. The favourable group also showed an improved median TTP (8 months vs. 2.6 months, p = 0.0007) and OS (16 months vs. 6 months, p = 0.0002). Conclusions: Our results suggest that prospective selection of candidates for cetuximab may be able to improve clinical outcome in patients with a favourable profile. This approach, if confirmed, may also allow an early switch to alternative treatment in patients with an unfavourable profile.
Bevacizumab plus chemotherapy continued beyond first disease progression in patients with metastatic colorectal cancer previously treated with bevacizumab-based therapy: Patterns of disease progression and outcomes based on extent of disease in the ML18147 study.
Authors: Greil Richard , Von Moos Roger , Bennouna Jaafar , Osterlund Pia J. , André Thierry , Van Cutsem Eric , Kubicka Stefan , Arnold Dirk , Vieitez de Prado Jose Maria , Bouche Olivier , Alonso Vicente , Borg Christophe , Schlichting Christoph , Steffens Claus-Christoph , Osborne Stuart , Waterkamp Daniel , Makrutzki Martina , Sastre Javier 
Published: March 2020

3604 Background: ML18147 demonstrated that bevacizumab (BEV) + chemotherapy (CT) continued beyond first disease progression (PD) significantly prolongs overall survival (OS) and progression-free survival (PFS) as second-line treatment for metastatic colorectal cancer (mCRC) [Bennouna et al. Lancet Oncol 2012]. Here we report exploratory analyses of patterns of PD and outcomes based on extent of disease. Methods: In ML18147, patients (pts) with unresectable, histologically confirmed mCRC who progressed ≤3 months after discontinuation of first-line BEV were randomised to second-line CT±BEV. This exploratory analysis evaluated PD patterns, time from discontinuation of study medications to PD, and survival outcome (OS, PFS) based on liver-limited vs extensive disease. Results: Details on patterns of PD and outcome by extent of disease are shown in the table. Conclusions: These exploratory analyses suggest that pts with liver-limited or extensive disease seem to benefit equally from BEV+CT continued beyond PD. Our findings indicate that the pattern of PD does not appear to differ between the two treatment arms following cessation of BEV treatment in this setting. Clinical trial information: NCT00700102. [Table: see text]
Association of KRAS mutation with worse recurrence-free survival and site of metastatic progression after resection of hepatic colorectal metastases.
Authors: Kemeny Nancy E. , Chou Joanne F. , Capanu Marinela , Gewirtz Alexandra N. , Cercek Andrea , Kingham T. Peter , Jarnagin William R. , Fong Yuman , DeMatteo Ronald P. , Allen Peter J. , Shia Jinru , Ang Celina , Vakiani Efsevia , D'Angelica Michael Ian 
Published: March 2020

3609 Background: There are conflicting results regarding the influence of KRAS mutation status and outcome in patients (pts) with colorectal cancer. A recent report suggested worse outcome in KRAS mutated (MUT) pts who underwent resection of hepatic metastases (Karagkounis et al, ASCO 2012). Methods: Recurrence patterns and survival were evaluated in 169 patients who had undergone resection of liver metastases, then received adjuvant hepatic arterial infusion and systemic chemotherapy, and for whom KRAS data were available. Kaplan-Meier methods were used to estimate recurrence free survival (RFS) and overall survival (OS). Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adjuvant therapy to bone, brain, lung and liver metastases separately. Mutations in KRAS (codons 12, 13) were detected using the iPLEX assay (Sequenom, Inc). Results: Median follow-up for the entire cohort was 38.8 months. 118 were KRAS wildtype (WT), and 51 were KRAS MUT (45 G12, 5 G13, 1 K117N). The 3 year RFS was 48% [95%CI: 37-58%] for KRAS WT pts and 30% [15-44%] for MUT pts (p<0.01). OS at 3 years was 96% [88-98%] for KRAS WT and 80% [61-90%] for MUT pts (p=0.08). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in Table 1. The cumulative incidence of metastases to bone at 2 years was 0% and 13.7% in KRAS WT versus MUT pts (p<0.01), to brain 0% versus 4.6% for KRAS WT versus MUT (p=0.05), and to lung 27% versus 47.5% in KRAS WT versus MUT pts (p<0.01). Conclusions: In pts who have had liver resection followed by adjuvant therapy, those with KRAS MUT have a worse RFS and seemingly worse OS than those who are KRAS WT. Also, patients with KRAS MUT appear more likely to develop bone, brain, and lung metastases. Further investigation of a larger number of patients is warranted. [Table: see text]
Analysis of NRAS mutation as poor prognostic indicator and predictor of resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Schirripa Marta , Loupakis Fotios , Cremolini Chiara , Morvillo Manfredi , Bergamo Francesca , Zoratto Federica , Salvatore Lisa , Antoniotti Carlotta , Marmorino Federica , Sensi Elisa , Lupi Cristiana , Fontanini Gabriella , De Gregorio Veronica , Giannini Riccardo , Basolo Fulvio , Masi Gianluca , Falcone Alfredo 
Published: March 2020

3613 Background: NRAS belongs to RAS family. NRAS mutations are mutually exclusive with KRAS and BRAF mutations and contribute to the activation of Ras/Raf/MAPK pathway. Previous experiences evaluated the prognostic/predictive role of NRAS mutations suggesting a poorer prognosis and resistance to anti-EGFRs for NRASmutant (mut) mCRC pts. The aim of the present study was to confirm such preliminary findings in a large cohort of mCRC pts. Methods: Data on KRAS (codons 12, 13 and 61) and BRAF-V600E mutational status of mCRC pts referred to our pathology from '09 to '12 were collected. NRAS mutational status (codons 12, 13 and 61) was evaluated in KRAS and BRAF wt pts. OS was calculated from date of diagnosis of metastatic disease. Data on response and PFS according to RECIST were collected for NRASmut irinotecan-refractory pts treated with anti-EGFRs +/- irinotecan. Results: 774 mCRC pts were included. KRAS/BRAF mutations were found in 384 (50%)/69 (9%) cases. NRAS was mut in 47 (15%) out of 318 KRAS and BRAF wt pts. NRAS mut pts had significantly shorter OS in comparison to KRAS-BRAF-NRAS wt pts (HR=0.60 [0.29-0.99] p=0.045). BRAF mut pts had significantly worse OS in comparison to NRAS mut pts (HR=1.75 [1.073-2.87] p=0.03). No difference was observed between NRAS mut and KRAS mut pts (HR=0.86 [0.51-1.43] p=0.61). 18 pts out of 47 NRAS mut pts received anti-EGFRs in advanced lines. 8 pts (7 cetuximab-based, 1 panitumumab monotherapy) were evaluable according to RECIST criteria and therefore eligible for the present analysis. None of them responded and only 1 SD was observed. Pooling our results with available data on anti-EGFRs’ activity in NRASmut pts in advanced lines of treatment (De Roock, 2010; Peeters, 2013; Andrè, 2012), only 1 response is described out of 35 treated pts (2,9%). Conclusions: Our data demonstrate that NRAS mutations have a relevant incidence in KRAS and BRAF wt mCRC pts. Present results are consistent with previous experiences and confirm that NRAS mutations affect prognosis of mCRC patients and predict lack of response to anti-EGFRs. Further insights into NRAS mut mCRC biology and prospective validation are warranted.
Primary prophylactic granulocyte colony-stimulating factor (GCSF) in Gilbert’s disease patients treated with FOLFIRI first line for metastatic colorectal cancer (mCRC): Final results of the FFCD 0604 study.
Authors: Lecomte Thierry , Bouche Olivier , oden-Gangloff Alice , Le Malicot Karine , Aparicio Thomas , Mitry Emmanuel , Bedenne Laurent , Deplanque Gael , Volet Julien , Tougeron David , Bonnetain Franck , Moreau Marie , Dorval Etienne , Loriot Marie-Anne , Laurent-Puig Pierre , Lepage Come 
Published: March 2020

3614 Background: Gilbert’s disease patients (pts) (homozygotous for the UGT1A1*28 allele) have a major risk (>30%) of severe, life-threatening, neutropenia when treated with Irinotecan (IRI). The aim of this study was to demonstrate that, in these pts, treated with IRI 1st line for mCRC, primary prevention with GCSF (lenograstim) reduces under 10% the risk of grade 4 or febrile neutropenia. Methods: This is a prospective, multicenter, phase II study of FOLFIRI + bevacizumab 1st line (IRI 180 mg/m² every 2 weeks) and primary prophylactic GCSF (D5 to D11 each course) in mCRC pts with Gilbert’s disease. Pre-chemotherapy UGT1A1 genotyping was centralized and standardized using a biological molecular technique applied on DNA blood-extracted lymphocytes. Using a 2-step Fleming design, (α=5% and β=90%), 30 pts had to be included with an interim analysis (IA) planned after 20 pts and 4 months of follow-up. Results: Twenty pts from 7 centers were included between 10/2007 and 02/2012 and 19 analysed for the IA. Median pts age was 63 years (range: 45-73), 60% were females, 90% were PS 0 or 1, 80% had a colic primary site and 73% hepatic metastases. The primary site was non- resected in 1/3 of pts. The total number of administered courses of chemotherapy was 229 with a median of 12 per pt (range: 1-40). Among all these courses, 213 were administered with GCSF. IRI was administered as defined by the protocol with a nearly 100% rate of received /theoretical dose. Grade 3 neutropenia rate was 10.5%. No grade 3-4 diarrhea, no grade 4 or febrile neutropenia and no toxic death were observed. No declared SAEs were related to GCSF. In term of best response at 6 months, 7 pts were in complete or partial response and 9 had stable disease. Median progression free survival and overall survival were respectively 8.7 months (4.9; 13.4) and 24.4 months (12.6; ND). Conclusions: This study is the first to demonstrate that a pharmacogenetic approach based on a simple genetic test easy to perform can achieve a high rate of safe and performant administration of IRI in high risk mCRC pts. Clinical trial information: NCT00541125.
Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer.
Authors: Senzer Neil N. , LoRusso Patricia , Martin Lainie P. , Schilder Russell J. , Amaravadi Ravi K. , Papadopoulos Kyriakos P. , Segota Zdenka E , Weng David Edward , Graham Martin , Adjei Alex A. 
Published: March 2020

3621 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs and has potent preclinical anti-tumor synergy combined with TNFa-inducing chemotherapies [i.e irinotecan (I)]. B and I combination is well-tolerated and has encouraging activity in a phase 1 study. This study tested B+I with an ascending dose strategy (ADS) of B to mitigate Bell’s palsy (BP) risk, an unusual and reversible side effect of SMAC mimetics. Methods: I at 350mg/m2 IV q3weeks was administered with B weekly (2 of 3 weeks). The dose of B was titrated incrementally during Cycle 1: C1D1 at 5.6mg/m2 and C1D8 at 11mg/m2 for ADS. For Cycle 2 (C2) and ongoing treatment, the B dose was 22mg/m2 or 35mg/m2, which were the MTD and DLT (BP) dose levels when combined with I from the Ph 1 study. Safety and clinical activity for KRAS mutant (KRAS-MT) and wild-type (KRAS-WT) were assessed in 3 cohorts: (1) at 22mg/m2 for CRC KRAS MT; (2) 22mg/m2 for CRC KRAS WT; (3) 35mg/m2 for CRC KRAS MT. Results: 51 patients (pts) with CRC had a median number of 4 prior regimens with 47 refractory/relapsed to irinotecan (92%). Tolerability was comparable to I alone. There were 2 PRs (4%), 27 SD (>2 cycles; 53%, median 4.7 mo), 17 PD (33%), and 5 non- evaluable pts (9%) for an overall clinical benefit (CR+PR+SD) rate of 57%. Median progression-free survival (PFS) was 2.1 months, and 6 mo PFS was 20%. KRAS MT CRC with prior I had a median PFS of 2.9 mo and 6 mo PFS of 25% (n=20). KRAS WT CRC with prior I had a median PFS of 1.4 mo and 6 mo PFS of 17% (n=18). The ADS seemed to reduce BP risk. No BP events occurred among 40 pts (22mg/m2 with ADS), compared to 1 of 7 pts (22mg/m2 without ADS). In the 35mg/m2 cohort, 1 BP event occurred among 12 pts (with ADS), compared to 3 of 6 (35mg/m2 without ADS). Conclusions: B + I demonstrated clinical benefit in pts refractory/relapsed to irinotecan, with greatest benefit in KRAS MT CRC. The ADS may provide a mitigation strategy for BP risk. Prior studies with I retreatment have showed no benefit in KRAS MT CRC. Comparable CRC pts with best supportive care have 6 mo PFS of 2%. Clinical activity supports the hypothesis for therapeutic synergy of B + I, with I as a TNFa-inducing agent. Further study of this combination is warranted. Clinical trial information: NCT01188499.