bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and toxicity of second-line AIO plus irinotecan (IRI) after pretreatment with AIO plus oxaliplatin (L-OHP) in the sequential therapy of metastatic colorectal cancer (CRC).
Authors: Wein Axel , Boxberger Frank , Siebler Juergen , Wolff Kerstin , Ostermeier Nicola , Busse Dagmar , Maennlein Gudrun , Hohenberger Werner , Neurath Markus F. , Hofheinz Ralf 
Published: March 2020

3561 Background: The FOLFIRI followed by FOLFOX6 (or vice versa) schedule has been considered as the gold standard of sequential treatment in CRC (Tournigand C. JCO 2004). In contrast to those bi-weekly schedules, the wide-spread weekly chemotherapy administration (e.g. AIO regimen), has not been investigated as yet for second-line treatment. The AIO + IRI schedule has provided promising results in the first-line treatment of CRC (Köhne C.-H. JCO 2005). Therefore, we now investigated the efficacy and toxicity of this schedule in second-line treatment in a phase II study. Methods: From 5/02 to 6/10, 60 palliative patients (pts.) with histologically proven CRC were enrolled in an oligocentric phase II study based on the following regimen: weekly IRI (80 mg/m2 i.v.) as 1h-infusion (inf.): d1, 8, 15, 22, 29, 36, qd 57 followed by 5-FU (2000 mg/m2 i.v.) combined with sodium folinic acid (500 mg/m2, d1, 8, 15, 22, 29, 36, qd 57) as a 24h-inf. via port-a-cath. This study focused on the efficacy and toxicity of second-line treatment with AIO + IRI. Results: Last date of evaluation: November 30, 2012; evaluable for efficacy: n = 58 pts., evaluable for toxicity: n = 59 pts.; men/women: 28/72%; median age: 65y; primary tumor location: rectum/colon: 45/55%.; toxicity data: higher grade toxicity (grade 3-4): leukocytopenia: 5.1%; thrombocytopenia: 1.7%; vomiting: 3.4%; diarrhea: 13.5%; hand-foot-syndrome: 1.7%; alopecia (grade 2) 3.4%; efficacy data: PFS: 4.2 m; median OS 14.2 m, RR: 10%; AIO + IRI following AIO + L-OHP achieved a median OS of 25.0 months. Conclusions: In the field of second-linetreatment of CRC the AIO plus IRI regimen offers both a favorable toxicity profile and promising results in terms of efficacy compared with the FOLFIRI regimen.
EGFL7 polymorphism to predict tumor response in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI and bevacizumab (BV).
Authors: Li Joseph Ethan , Zhang Wu , Loupakis Fotios , Yang Dongyun , Wakatsuki Takeru , Ning Yan , Stintzing Sebastian , El-Khoueiry Rita Elie , Volz Nico Benjamin , Marmorino Federica , Schirripa Marta , Salvatore Lisa , Antoniotti Carlotta , Cremolini Chiara , Lenz Heinz-Josef 
Published: March 2020

3565 Background: Angiogenesis involves endothelial cell (EC) sprouting, proliferation, and differentiation and recruitment of mural cells to stabilize new vessels. The proteins Epidermal Growth Factor Domain-Like 7 (EGFL-7) and Activin Receptor-like Kinase 1 (ALK1) play critical roles. EC-secreted EGFL7 antagonizes Notch to promote EC proliferation, sprouting, and motility. EGFL7 also regulates mural cell recruitment and extracellular matrix deposition. ALK1 is an EC-restricted TGF-β Type 1 receptor with downstream repression of Vascular Endothelial Growth Factor (VEGF) signaling. ALK1 also promotes pericyte-EC adhesion. EGFL7 or ALK1 inhibition enhances antitumor efficacy when combined with BV in murine models. Both are overexpressed in many cancers and may be critical for efficacy of anti-VEGF therapy. We tested whether EGFL7 (rs1051851, rs2297538) and ALK1 polymorphisms (rs2293094, rs11169953, rs706819) will predict efficacy of BV-based therapy in mCRC pts. Methods: Genomic DNA was extracted from peripheral whole blood samples from 455 mCRC pts treated with first-line BV and FOLFIRI. SNPs were analyzed by PCR-based direct DNA sequencing and evaluated for association with tumor response rate (RR), overall survival (OS), and progression free survival (PFS). Results: Male/female: 272/183; median age: 62 (range: 25-81); median PFS and median OS: 10.9 (95%CI: 10.1-11.6) and 29.9 (95%CI: 25.9-34.6) months, respectively; response to therapy: 59% (215 pts); median follow-up:23.6 (range: 1.8-60.4) months. Pts carrying the EGFL7 rs1051851 G/G alleles had a 62% RR versus 56% in pts with A/G and 29% in patients with A/A (p=0.0130, Cochran-Armitage trend test). The result remained significant after adjustment for baseline pt characteristics (p=0.026, Multivariable logistic regression test). There was no statistically significant association between tested polymorphisms and OS or PFS. Conclusions: The EGFL7 SNP rs1051851 may predict tumor response in mCRC pts treated with FOLFIRI and BV. To our knowledge, this is the first study demonstrating predictive significance of genetic variations in EGFL7. Prospective validation of this study is warranted.
Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer.
Authors: Klingbiel Dirk , Missiaglia Edoardo , Yan Pu , Tejpar Sabine , Roth Arnaud , d'Ario Giovanni , Delorenzi Mauro , Bosman Fred 
Published: March 2020

3577 Background: Studies on the association between colorectal cancer (CC) outcome and thymidylate synthase expression have provided inconsistent results. In this study we attempted to resolve the issue by assessing the associations between TS expression and outcome in a population of primary CC patients (pts), who after resection were randomized to 5-FU/FA vs. FOLFIRI adjuvant therapy. Methods: Immunohistochemical staining for TS protein was successfully performed for 1211 pts in the PETACC3 trial. TS immunoreactivity was scored as high expression (≥75% positive) and low expression (<75% positive). Gene expression respectively copy number data were available for 853 respectively 306 of these samples. Twelve single nucleotide polymorphisms (SNPs) close to the TYMS gene were assessed in 923 pts. Association of variables with relapse-free (RFS) and overall survival (OS) was assessed using Cox regression models. Results: High TS expression and RNA level were strongly associated (log fold change 0.65, p<0.001). Both were significantly higher in proximal CC. As expected, both were associated with other characteristics of proximal CC: MSI, BRAF mutation, high tumor grade. RNA was significantly correlated with gene copy number, distal CC showing more frequent allelic loss. Three SNPs were associated with gene expression which was validated in data from the 1000 genomes project, but none with survival. High TS expression was more strongly associated with better OS in pts receiving FOLFIRI (HR 0.4, 95% CI 0.3–0.6, p<0.001), than 5-FU/FA (HR 0.8, 95% CI 0.5–1.1, p=0.13), with a significant interaction (p=0.05). Similar results were observed for RFS (HR 0.5, p<0.001 vs. HR 0.7, p=0.07; interaction p=0.11). TS expression is still highly prognostic in multivariate models adjusting for factors associated with risk or proximal tumors in FOLFIRI treated pts (OS: HR 0.5, p=0.008; RFS: HR 0.6, p=0.02), but not in F-FU/FA treated pts (OS and RFS: HR=1, p=1). Conclusions: TS expression is lower in distal CC, partly due to deletion of the TYMS locus. Pts with high TS expression have longer RFS and OS, notably when treated with FOLFIRI. For these pts addition of irinotecan to 5-FU/FA adjuvant chemotherapy might be considered. Clinical trial information: NCT00026273.
Small bowel adenocarcinoma phenotyping and prognostic factors.
Authors: Aparicio Thomas , Svrcek Magali , Laforest Anais , Zaanan Aziz , Beohou Kanean , Afchain Pauline , Mitry Emmanuel , Taïeb Julien , Di Fiore Frédéric , Gornet Jean-Marc , Thirot-Bidault Anne , Sobhani Iradj , Malka David , Lecomte Thierry , Locher Christophe , Bonnetain Franck , Laurent-Puig Pierre 
Published: March 2020

3585 Background: SBA is a rare tumor with poor prognosis. Data regarding SBA molecular alterations are lacking. Methods: We searched for several candidate oncogenic alterations and characterised the immunophenotype according to the primary tumour location in pts with SBA (all stages; ampullary tumours excluded) treated in 11 centres from 1996 to 2008. Tissue microarrays were constructed from tumour samples, and DNA was extracted from formalin-fixed, paraffin-embedded samples. HER2, β-catenin, TP53, and mismatch repair (MMR) protein expression was assessed by immunohistochemistry. A molecular analysis assessed microsatellite instability, KRAS mutation and BRAFV600E mutation. Results: We obtained samples from 63 SBA pts (median age, 58 years; tumour stage: I-II, n=19 (30%); III, n=22 (35%); IV, n=20 (32%); locally advanced, n=2 (3%)). HER2 overexpression (3+) was observed in 2/62 (3%) pts. Overexpression of TP53 was observed in 26/62 (42%) pts. Abnormal expression of β-catenin was observed in 12/62 (19%) pts. MMR deficiency (dMMR) was observed in 14/61 (23%) pts, consistent with Lynch syndrome in 7/14 (50%) pts. All of the dMMR tumours were in duodenum or jejunum. Only one of dMMR tumour was stage IV. A KRAS mutation was observed in 21/49 (43%) pts. BRAFV600E mutation was observed in only 1/40 pt. Median overall survival (OS) was 36.6 months (95% confidence interval [CI], 26.9-72.2). In univariate analysis, stage I-II (p<0.001) and dMMR phenotype (p=0.02) were significantly associated with longer OS. In multivariate analysis, only disease stage independently predicted longer OS (p<0.001). For stage IV pts, median OS was 17.9 months (CI, 12.6-36.6). For stage I-III pts median recurrence-free survival (RFS) was 26.7 months (CI: 14.6-42.4). A trend for a better RFS was observed if tumour was dMMR HR: 0.39 (CI, 0.10-1.44], p=0.15. Conclusions: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high rates of KRAS mutations. The seemingly higher rate of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA in pts. A trend for good prognosis was associated with dMMR.
Estrogen and colorectal cancer incidence and mortality in the Women's Health Initiative clinical trial.
Authors: Lavasani Sayeh Moazami , Chlebowski Rowan T. , Prentice Ross L , Kato Ikuko , Wactawski-Wende Jean , Johnson Karen , Young Alicia , Hubbell F Allan , Simon Michael S. 
Published: March 2020

3594 Background: The preponderance of observational studies associate estrogen alone use with lower colorectal cancer incidence. In contrast, no difference in colorectal cancer incidence was seen in the Women's Health Initiative (WHI) randomized, controlled trial (RCT) of estrogen versus placebo after 7.1 years mean intervention. We now assess the influence of estrogen alone use on longer-term colorectal cancer incidence and mortality after an additional 5.6 years post-intervention follow-up. Methods: The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 10,739 postmenopausal women who had undergone prior hysterectomy and who were randomly assigned to receive daily 0.625 conjugated equine estrogen (n = 5279) or matching placebo (n = 5409). Colorectal cancer diagnosis rates and mortality were assessed after a mean of 7.1 years (standard deviation [SD] 1.1) of intervention and 12.7 years follow-up. Results: Colorectal cancer incidence in the treatment and control groups were almost equivalent, 0.15% diagnoses/year v 0.13% in the estrogen therapy arm and the placebo group, respectively (Hazard ratio [HR], 1.12; 95% Confidence Interval [CI], 0.83-1.52; P = 0.46). Bowel screening examinations were comparable in both groups throughout. For women age 70-79 at study entry, hormone therapy was associated with an increased risk of colorectal cancer, HR 1.71; 95% CI, (1.02-2.86). For women age 50-59 and 60-69, the respective HR’s and 95% CI were 0.86 (0.43-1.71) and 0.98 (0.64-1.49), p-interaction 0.165. For women with a waist circumference of > 88 cm, there was an increased risk of colorectal cancer, HR 1.53; 95% CI, 0.95-2.45 compared to 0.95 (0.66-1.39) for waist circumference of < 88 cm, p-interaction 0.124. Although not statistically significant, there was a higher number of colorectal cancer deaths in the hormone therapy arm (33 v 24 deaths; 0.05% v 0.04%; HR, 1.42; 95% CI, 0.84-2.41; P = 0.19). Conclusions: There were no significant differences in colorectal cancer incidence or mortality after long-term follow-up in the WHI RCT of conjugated equine estrogen. There was a suggestion of an elevation in colorectal cancer risk among older women randomized to estrogen. Clinical trial information: NCT00000611.
Prognostic significance of tumor stromal and epithelial claudin 2 in metastatic colorectal cancer.
Authors: Mezheyeuski Artur , Guren Tormod Kyrre , Glimelius Bengt , Pfeiffer Per , Kure Elin , Ikdahl Tone , Skovlund Eva , Sorbye Halfdan , Tveit Kjell Magne , Pietras Kristian , Sandstrom Per , Bojmar Linda , Portyanko Anna , Ostman Arne 
Published: March 2020

3597 Background: Tight junctions (TJ) are the most apical epithelial cell–cell adhesions. Claudin super-family trans-membrane proteins, including claudin 2 (cl2), are important components of TJs. Expression of cl2 has been reported to be elevated in colorectal cancer (CRC) and its up-regulation increases tumorigenicity of CRC cells in vitro. The aim of this study was to analyze the prognostic significance of cl2 in CRC. Methods: A tissue microarray (TMA) from the stage IV CRC patients of the phase III NORDIC-VII study was used. Cl2 IHC staining was evaluated in a semi-quantitative manner in cancer cells (cl2-C) and in the tumor stroma (cl2-S). Primary fibroblasts were established from human CRC tumor tissue and non-tumor colon tissue, and evaluated by immunoblotting. Results: Analyses of the TMA derived from the NORDIC-VII cohort revealed that cancer cell expression and tumor stroma expression of cl2 was associated with shorter OS in a Log-Rank test for trend (cl2-C, n=315, p=0.018; cl2-S, n=319, p=0.020). Expression of cl2-S, but not cl2-C was prognostic in multivariate analysis including WHO performance status, alkaline phosphatase level and BRAF mutation status (HR=1.30; 95% CI 1.08-1.56; p=0.006). When cl2-C and cl2-S expression was combined the prognostic significance was increased. The group with high cl2-C and high cl2-S (N=182), when compared with the rest of the cases (n=129), displayed a worse prognosis in terms of OS (19.1 mo vs 27.2 mo; p=0.003) in univariate analyses (HR=1.55, 95% CI 1.16-2.08, p=0.003) and in multivariate analyses (HR=1.52, 95% CI 1.13-2.05, p=0.006). Immunoblotting analysis of primary cultures of fibroblasts confirmed cl2 expression in fibroblasts from CRC tissue and from non-tumor tissue, with higher expression observed in the tumor fibroblasts. Conclusions: CRC display a previously un-reported stromal expression of cl2 of prognostic significance. High cl2-S is associated with worse prognosis in patients with metastatic CRC, in a manner independent of WHO status, alkaline phosphatase levels and BRAF status. Furthermore, high expression of cl2 in both cancer cells and the tumor stroma is also associated with poor prognosis.
Hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil, and oxaliplatin plus intravenous cetuximab (Cet) (Optiliv) after failure on one versus two or three chemotherapy protocols in patients (pts) with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) (European phase II clinical trial NCT00852228).
Authors: Ducreux Michel , Innominato Pasquale F. , Hebbar Mohamed , Smith Denis Michel , Lepère Céline , Focan C. N. J. , Guimbaud Rosine , Carvalho Carlos , Tumolo Salvatore , Awad Sameh , Truant Stephanie , Castaing Denis , Karaboué Abdoulaye , De Baere Thierry , Kunstlinger Francis , Bouchahda Mohamed , Boige Valerie , Rougier Philippe , Adam Rene , Levi Francis ,   ARTBC International
Published: March 2020

3599 Background: Optiliv allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, despite failure of 1-3 prior chemotherapy protocols (Lévi et al. Proc ASCO GI 2013). Purpose: To assess tolerability and efficacy of Optiliv according to previous chemotherapy exposure. Methods: Pts received iv Cet (500 mg/m²) and chronomodulated or conventional HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 wks. Liver surgery was performed according to q6wks multidisciplinary reviews. Pts were categorized according to Optiliv as 2nd (N=29 pts) vs 3rd-4th chemotherapy line (N=35 pts). Results: Pt characteristics were similar in both groups. Overall, there were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2) and predominantly liver lesions. LM-CRC were bilateral in 51 pts (79.7%), with a median of 10 metastases (1-50), 6 segments involved (1-8), and largest diameter of 52 mm (15-172). 61 pts (2nd line, 27; 3rd-4th line, 34) received a median of 6 courses (1-15). Grade 3-4 toxicities per pt were similar in both groups except for abdominal pain (2nd line, 15% vs 3rd-4th line, 35%, p=0.07), diarrhea (7% vs 24%, p=0.09), thrombocytopenia and febrile neutropenia (0 vs 9%, p=0.25). Four CR were achieved in 2nd line (15%) vs none in 3rd-4th line. Respective objective response rates were 63% and 38% (p=0.05). R0-R1 resections were performed in 11/27 pts (41%) on 2nd line vs 6/34 pts (18%) on 3rd-4th line (p=0.06), resulting in respective median progression-free survival (PFS) of 14.2 months [7.8 - 20.7] vs 7.3 [5.5 - 9.1] (p=0.002). Median overall survival (OS) was not reached at 3 years in the pts on Optiliv as 2nd line vs 15.2 months in the more heavily pretreated pts (p<0.001). Conclusions: Intravenous Cet and triplet hepatic artery infusion resulted in the doubling of secondary surgical resection rate of LM-CRC, PFS and OS in 2nd lineas compared to 3rd-4th line. Optiliv now deserves upfront testing. Clinical trial information: NCT00852228.
Prevention of 5-FU-induced health-threatening toxicity by pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.
Authors: Boisdron-Celle Michele , Capitain Olivier , Metges Jean-Philippe , Faroux Roger , Borg Christophe , Galais Marie-Pierre , Kaassis Mehdi , Bennouna Jaafar , Bouhier Leporrier Karine , Francois Eric , Baumgaertner Isabelle , Guerin-Meyer Veronique , Cojocarasu Oana , Roemer-Becuwe Celia , Stampfli Claire , Rosenfeld Ludovic , Lecomte Thierry , Berger Virginie , Morel Alain , Gamelin Erick 
Published: March 2020

3601 Background: While 5-FU is the foundation of many in GI oncology treatments, pts with DPD deficiency can experience early-onset severe (5%) even fatal (0.3%) toxicities. This study aimed to confirm the pharmaco-economic benefits of pre-therapeutic screening for DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (NCT01547923). Methods: Two parallel cohorts of pts treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD deficiency screening; Group B: no evaluation. Enrollment was based on 5-FU administration guidelines of each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) (1,2,3). The 2 groups were to be compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed in the case of proven 5-FU-related toxic death. Results: 1,130 pts were included from 06/01/2008 to 07/31/2012. Group A: no severe toxicity despite 1 pt with complete deficiency (pt not treated with 5-FU), 20 pts with partial deficiency had safe PK-monitored 5-FU (ODPM Protocol) with only one hospitalization due to toxicity. Group B: One death due to complete DPD deficiency, confirmed retrospectively. Enrollment prematurely closed after experts’ unanimous decision citing ethical concerns. 21 pts with partial DPD deficiency. 5 reported toxicity-related hospitalizations. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A pt had safe treatment whereas Group B pt died due to 5-FU toxicity. Pre-therapeutic DPD deficiency screening using this multi-parametric approach should be performed before 5-FU-based treatment and PK-guided dose adaptation allows for safe treatment of even partially DPD deficient patients. Clinical trial information: NCT01547923. [Table: see text]
Impact of early tumor shrinkage on clinical outcome in KRAS wild-type colorectal liver-limited metastases treated with cetuximab plus chemotherapy: Lessons from a randomized controlled trial.
Authors: Ye Le-chi , Zhong Yunshi , Liu Tianshu , Wei Ye , Ren Li , Zhu Dexiang , Qin Xinyu , Fan Jia , Chen Jingwen , Chang Wenju , Lin Qi , Xu Jianmin 
Published: March 2020

3610 Background: Recently, early tumor shrinkage (ETS) was reported to predict outcome in metastatic colorectal cancer treated with cetuximab (cet). This study was to evaluate the impact of ETS on long-term outcome in patients (pts) with wild-type-KRAS unresectable CLLM receiving cet plus chemotherapy (CT, FOLFIRI or mFOLFOX6). Methods: 138 pts treated in a randomized controlled trial (70 in armA received CT plus cet and 68 in armB received CT alone) previously reported (Jianmin et al, ESMO 2012, abstract-557, ClinicalTrials.gov, number NCT01564810) were included into this analysis. ETS was defined as a reduction of ≥20% in the sum of the longest diameters of target lesions compared to baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and overall survival (OS). Results: 132 pts were available for evaluation, and ETS occurred more frequently in armA than that in armB (45/68 vs. 26/64, p= .003). Irrespective of treatment arm, pts achieved ETS were associated with longer OS (armA: 38.0 vs. 18.7months, p< .001; armB 30.6 vs.17.7months, p= .003) and PFS (armA: 11.8 vs. 4.8months, p< .001; armB 8.0 vs.4.6months, p= .001) when compared to pts with no-ETS. Among pts with ETS, there were statistic difference between armA and armB in terms of PFS (11.8 vs. 8.0months, p= .041) but not of OS (38.0 vs. 30.6months, p= .30); the converted resection rates for liver metastases were 40.0% (18/45) in armA and 19.2% (5/26) in armB, which were no significantly different (p= .072). For pts without liver surgery, pts observed ETS also gained an increased survival benefit over those no-ETS in armA with regards to OS (p= .01) and PFS (p< .001) though it was not full certified in armB (OS: p= .054; PFS: p= .041). For pts in armA, cet-induced skin toxicity correlated with the occurrence of ETS (p= .048). In addition, cox regression for OS using indicated a hazard ratio of 0.39 (95%CI 0.21–0.72, p = .003). Conclusions: ETS ≥20% at 8 weeks may serve as a predictor of favorable outcome in pts with wild-type-KRAS CLLM receiving cet plus CT.