bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic effects of circulating markers of epithelial mesenchymal transition (EMT) in metastatic colorectal cancer patients.
Authors: Shah Neeraj Nailesh , Lieu Christopher Hanyoung , Ivan Cristina , Overman Michael J. , Shimizu Masayoshi , Morris Jeffrey , Tran Hai T. , Heymach John , Calin George , Kopetz Scott
Published: February 2017

456

Background: EMT is a phenotypic description of cancer cells that include loss of cell adhesion, increased motility, invasion, and chemoresistance. EMT gene signature is a poor prognostic feature in colon cancer. Circulating markers to decipher the EMT signature in colorectal cancer patients (CRC pts) would therefore be of clinical relevance. Studies have shown that miR-21, IL-6 and IL-8 have been associated with EMT in cancer cells in vitro and their expression has been shown to be highly correlated in primary colon cancer tissue

Methods: Plasma samples were obtained from two mCRC cohorts: 120 pts with unresectable metastases, and 91 pts who subsequently underwent partial hepatectomy with curative intent. Circulating levels of IL-6, IL-8 and miR-21 (normalized by miR-16) were measured, and dichotomized using previously published cutoffs. Pts with high levels of ≥2 of 3 EMT markers were categorized as having an EMT phenotype. Survival analysis was by log-rank and proportional hazard.

Results: As previously seen in colon tissue, miR-21, IL-6 and IL-8 expression were correlated in plasma samples (P<0.001) and individually associated with shorter overall survival (P<0.05). The EMT phenotype, present in 44% of both cohorts, was a strong predictor of poor overall survival in the unresectable cohort (HR 2.6, 95% CI 1.6 to 4.1, median OS 15.5 mo v 27.1 mo, P<0.001) as well as in the validation resectable cohort(HR 3.8, 95% CI 1.9 to 7.7, median OS 41.5 mo vs 81.9 mo, P<0.001). This effect was sustained in a multivariate analysis after adjustment for tumor volume and clinical characteristics (HR 1.92, P=0.009 in unresectable cohort and HR 3.53, p=0.002 in hepatectomy cohort). The EMT phenotype was also predictive of shorter progression-free survival (HR 2.2, 15.8 mo vs 7.8 mo, P=0.02) and relapse-free survival (HR 2.1, 18.4 mo vs 31.4 mo, P=0.01) in the two respective cohorts, consistent with prior preclinical data correlating EMT with chemoresistance

Conclusions: As surrogates of EMT, circulating levels of miR-21, IL-6 and IL-8 are co-expressed in plasma of mCRC pts and can be used to predict overall survival and benefit from chemotherapy. This finding highlights the clinical relevance of EMT in colon cancer biology
Relationship of incomplete inhibition of PI3K pathway signaling and efficacy of cetuximab in KRAS wild-type colorectal cancers.
Authors: Corcoran Ryan Bruce , Ebi Hiromichi , Ryan David P. , Meyerhardt Jeffrey A. , Engelman Jeffrey A.
Published: February 2017

462

Background: Therapies targeting receptor tyrosine kinases (RTKs) are typically effective only when they lead to simultaneous downregulation of PI3K-AKT and MEK-ERK signaling. Cetuximab is a monoclonal antibody directed against EGFR that has been approved for the treatment of metastatic colorectal cancer, and several studies have suggested that its benefit is restricted to patients with KRAS wildtype cancers. However, even in KRAS wildtype colorectal cancers, the response rate to single-agent cetuximab is low, and the mechanistic basis for this is not well-understood.

Methods: The ability of cetuximab to downregulate PI3K-AKT and MEK-ERK signaling in a panel of KRAS wildtype colorectal cancer cell lines was assessed by immunoblotting. We preformed immunoprecipitations of the regulatory subunit of PI3K on lysates derived from cell lines and primary colorectal tumor specimens to identify the RTKs involved in PI3K activation. Cetuximab-based therapeutic combinations were evaluated in KRAS wildtype cell lines and tumor xenograft models.

Results: Cetuximab led to effective inhibition of MEK-ERK signaling (>75% reduction in phospho-ERK), but led to incomplete inhibition of PI3K-AKT signaling (0-50% reduction in phospho-AKT) in all KRAS wildtype colorectal cell lines tested. PI3K regulatory subunit immunoprecipitations revealed multiple RTK inputs to PI3K in cell lines and primary tumors, most notably from IGFIR. Combined treatment with cetuximab and an IGFIR inhibitor or a PI3K inhibitor led to improved efficacy in vitro and in tumor xenograft models.

Conclusions: Cetuximab fails to completely downregulate PI3K-AKT signaling in KRAS wildtype colorectal cancer cell lines. Biochemical analysis of cell lines and primary colorectal tumors reveals that additional RTKs other than EGFR play a role in PI3K activation in these cancers. Therefore, combining cetuximab with targeted therapies directed against the PI3K pathway may lead to improved efficacy in KRAS wildtype colorectal cancers.
NTRK3 as a novel tumor suppressor gene in colorectal cancer.
Authors: Luo Yanxin , Kaz Andrew , Kanngurn Samornmas , Grady William M.
Published: February 2017

469

Background: Neurotrophin tyrosine kinase receptor 3 (NTRK3) is a receptor tyrosine kinase that has been shown to be an oncogene in breast cancer and possibly in hepatocellular carcinoma. NTRK3 is a trophic dependence receptor, which is a recently described class of receptors that initiate signaling in both the ligand bound and unbound states. Through a genome-wide screen for aberrantly methylated genes, we identified aberrantly methylated NTRK3 as a frequently methylated gene in colon cancer. The aim for the present study is to determine if NTRK3 is an epigenetically silenced tumor suppressor gene in colorectal cancer.

Methods: NTRK3 promoter methylation was analyzed in human colon cancer cell lines, normal colon epithelium tissue, colorectal adenomas and colorectal cancers using quantitative methylation-specific PCR and bisulfite sequencing. NTRK3 mRNA and protein expression were studied using quantitative real-time PCR, immunohistochemistry and western blotting respectively. The tumor suppressor function of NTRK3 was examined by assessing the effect of NTRK3 on cell apoptosis, cell migration and in vitro colony formation assays in colon cancer cell lines stably transfected with an NTRK3 expression construct in the presence or absence of NT-3.

Results: NTRK3 is methylated in 60% of colon adenomas and in 57% of colorectal cancers. The aberrant methylation of NTRK3 suppresses NTRK3 expression and releases colon cancer cells from NTRK3 mediated apoptosis induced by the expression of NTRK3 in the absence of the ligand NT-3 via the activation of MAPK/ERK pathway. Methylation of NTRK3 also releases colon cancer cells from NTRK3 mediated suppression of motility and anchorage independent growth. The addition of NT3 to colon cancer cells transfected with NTRK3 inhibits the tumor suppressor effects of NTRK3.

Conclusions: The aberrant methylation of NTRK3 is likely functionally relevant for colorectal cancer formation as NTRK3 appears to be a conditional tumor suppressor gene in the colon depending on the expression status of its ligand NT-3. NTRK3 is a novel aberrantly methylated conditional tumor suppressor gene that is frequently methylated in colon adenomas and cancers and whose discovery reveals possible novel treatment approaches to colon cancer.
HER2/neu expression in locally advanced rectal cancer cUICC II/III and its correlation with long-term prognosis.
Authors: Conradi Lena-Christin , Styczen Hanna , Sprenger Thilo , Becker Heinz , Ghadimi Michael B. , Beissbarth Tim , Middel Peter , Liersch Torsten
Published: February 2017

493

Background: With the implementation of multimodal treatment strategies including neoadjuvant radiochemotherapy (RCT), the prognosis of locally advanced rectal cancer has been improved over the last two decades. Most actual clinical trials aim to further develop therapy by intensification of agents administered. We examined Her2/neu in rectal cancer patients to evaluate its expression as a potential drug target as well as its capacity as predictive and prognostic biomarker.

Methods: Two-hundred-seventy-seven patients (205 male, 72 female; median age 63.5 years) with locally advanced rectal cancer (cUICC-II/III) were included in this study. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 236 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. All patients were treated within phase-II/-III-trials of the German Rectal Cancer Study Group or analogous to these standardized protocols. Her2-/neu expression from pre-treatment biopsies and corresponding resection specimens were assessed by immunohistochemical staining and SISH-analysis.

Results: A positive Her-2/neu expression was found in 12.3% of all pre-treatment tumor biopsy samples and in 28.7% of the resection specimens. The correlation of the pre-treatment Her-2/neu status did not show a significant correlation with the grade of tumor regression. However, patients with a higher Her-2/neu protein expression as measured in the resection specimen showed a significant survival benefit (p=0.0277) compared with patients having low intratumoral Her-2/neu expression during the follow-up (median 43 months). The 10-year survival rate was 73.2% (Her-2/neu positive) versus 60.1% (Her-2/neu negative).

Conclusions: The proportion of patients with a positive Her-2/neu status is relevant in rectal cancer. Her-2/neu might potentially serve as a promising drug target in rectal cancer and should be further assessed within prospective clinical trials. Furthermore the Her-2/neu status seems to be a valuable prognostic marker within the multimodal treatment of advanced rectal cancer.
Genetic differences based on miRNAs of colorectal adenocarcinoma according to age and the presence or absence of MMR defect.
Authors: Guillen-Ponce Carmen , Conde Moreno ELISA , Aguado Elia , Soto Jl , Alenda Cristina , Castillejo Adela , Barbera Victor M , Salas Dolores , Carrato Alfredo , Garcia Bermejo Maria LAURA
Published: February 2017

495

Background: More than 1.2 million new cases of colon adenocarcinoma (CRC) are diagnosed annually. Specific germline mutations are responsible for hereditary CRC syndromes, while somatic mutations is thought to underlie most sporadic cases. Recently, miRNAs have been described as important regulators of malignant transformation. We aim to study the expression of miRNAs in CRC patients with Lynch syndrome and in patients with CRC without microsatellite instability (MSI-S) who have developed cancer at different ages.

Methods: We included 60 cases of CRC patients: 20 with CRC associated with Lynch syndrome in carriers of germline MMR mutation (group 1), 20 with CRC MSI-S diagnosed before 45 years (group 2) and 20 with MSI-S diagnosed after age 50 (group 3). From all these cases we selected 7: 3 from group 1, 2 from group 2, another 2 from group 3, and a control with healthy colonic mucosa. Screening was carried out for expression of miRNAs (850 miRNAs) and hybridization arrays (Exiqon) using paraffin colic tissue. A comparative analysis was made of the expression obtained in the different groups.

Results: Hybridization arrays analysis indicates that there are 248 miRNAs differentially expressed between healthy controls and patients with CRC. In addition, there are 165 miRNAs differentially expressed between different groups of patients with CRC according to age at diagnosis (≤ 45 years vs.> 50 years). Moreover, the pattern of miRNAs in patients with germline mutation in Lynch syndrome is very different to that of patients diagnosed with CRC> 50 years. There are 117 miRNAs differentially expressed between these cases. Just a group of 20 miRNAs have different expression among patients with CRC MSI-S ≤ 45 years for CRC patients with Lynch syndrome mutation in MLH1.

Conclusions: Differences exist in the profile of CRC mRNAs expression according to the age, as well as between CRC MSI-S patients > 50 years and CRC in Lynch syndrome. Different patterns of miRNAs in CRC indicate different molecular signature in different groups of CRC could became new CRC diagnostic markers and most importantly could point out new targets for therapeutic interventions in CRC.
Feasibility study of irinotecan based on UGT1A1 polymorphisms for metastatic colorectal cancer: Interim report.
Authors: Kashihara Hideya , Shimada Mitsuo , Kurita Nobuhiro , Nishioka Masanori , Iwata Takashi , Sato Hirohiko , Morimoto Shinya , Yoshikawa Kozo , Miyatani Tomohiko , Mikami Chie
Published: February 2017

505

Background: Although Irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Previously, we showed UGT1A1 polymorphisms in Japanese patients (2011 ASCO-GI). Here, we present the interim report of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC.

Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 30 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2. The incidences of severe toxicities in each gene type of UGT1A1 and the response rate in FOLFIRI therapy were investigated.

Results: In Japanese people, UGT1A1*6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%). On the 30 patients with advanced CRC treated with FOLFIRI, the genotypes of UGT1A1*28 were homozygous in 1 (3%) and heterozygous in 6 (20%), *6 were homozygous in 0 and heterozygous in 8 (27%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (38%). In *28 heterozygous patients, 1 patient (17%) showed severe toxicities. There was no decrease of irinotecan doses in each group. The number of course to PD was 7.6 (1-23). Regarding the response rate, PR, SD, PD was observed in 2 (7%), 6 (20%) and 18 patients (60%), respectively.

Conclusions: In our interim report, the dosages of irinotecan based on UGT1A1 polymorphisms are safety in FOLFIRI therapy.
A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients.
Authors: Makihara Katsuya , Mishima Hideyuki , Azuma Sayaka , Matsuyama Kazuyo , Komori Katsuya , Hasegawa Hiroko , Yasui Masayoshi , Ikenaga Masakazu , Tsujinaka Toshimasa
Published: February 2017

510

Background: Pharmacokinetically (PK) guided dose adjustment of 5-fluorouracil (5-FU) has been reported better than body surface area based dosing of 5-FU. On the other hand, few articles have been reported about PK guided dose management of oral drug chemotherapy. The aim of this study is to assess the possibility of pharmacokinetically guided dose management of capecitabine with a nanoparticle antibody-based immunoassay for 5-FU (My5-FUR assay).

Methods: Colorectal cancer patients receiving chemotherapy with FOLFOX, FOLFIRI, LV5FU2, Capecitabine, CapeOx (capecitabine plus oxaliplatin) were analyzed by My5-FUR assay. Blood samples were collected after 24 hours of 5-FU infusion or 2 hours after administration of capecitabine at day 7. Correlation between liquid chromatography-mass spectrometry (LC-MS) and My5-FUR assay of 5-FU were also examined.

Results: A total of 50 patients were analyzed by My5-FUR assay. A linear relationship (r=0.9204) exists between LC-MS and My5-FUR assay. The area under the concentration curve of continuous 5-FU infusion were 15~56mg-h/L, and the concentrations of 5-FU after administration of capecitabine were 41~457 ng/mL. Severe side effects were observed in the patients with plasma concentration of 5-FU greater than 300 ng/mL 2 hours after administration of capecitabine.

Conclusions: Plasma concentrations of 5-FU after administration of capecitabine were measurable by My5-FUR assay. The concentrations of 5-FU were lower in capecitabine than continuous 5-FU. The distribution of 5-FU was wider in capecitabine than continuous 5-FU. It is possible to manage dose of capecitabine pharmacokinetically.
Use of wild-type (wt) KRAS, BRAF, and PIK3CA, combined with KRAS mutations (mut) in codon 13 and RNA expression level of amphiregulin (AREG) and epiregulin (EREG), to predict cetuximab (CE) response with high accuracy in colorectal cancer of all four Dukes' stages.
Authors: Pechanska Paulina , Mayr Tobias , Hinzmann Bernd , Klaman Irina , Daniel Abd el Messih Suzette , Becker Michael , Hoffmann Jens , Rosenthal Andre
Published: February 2017

517

Background: wt KRAS and wt BRAF are established clinical markers to predict response to CE in patients (pts) with mCRC. Some pts with KRAS mut in codon 13 respond to CE, while the majority of them do not. Recently, it was shown that pts with CRC of Duke C and wt KRAS and wt BRAF do not benefit from CE added to FOLFOX (ASCO 2011 abstr 3607). In addition, data indicated that AREG and EREG RNA expression is also correlated with CE response. We established a panel of 133 xenograft models from primary tumor tissue of pts with CRC of all four Dukes stages and conducted a therapy experiment with CE (AACR '11, LB9086).

Methods: mut status of KRAS (G12, G13, A146T); BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allele-specific RT-PCR. KRAS codon 61 was sequenced. AREG and EREG expression levels were analyzed by RT-PCR expression assays.

Results: We observed response to CE (treated to control ratio < 20%) in 18/67 (27%) of the treated xenografts. The distribution of responder (R) to non-responder (NR) is: Duke A: n=8; 2R / 6NR; B: n= 22; 8R / 14NR; C: n=28; 4R / 24 NR; D: n= 9; 4R / 5NR. Retrospective classification based on KRAS mut status identified R with a sensitivity (S+) of 83%, and NR with a specificity (S-) of 61%. If mut status in BRAF and PIK3CA were added the classifier showed S+ of 83% / S- of 78%. If any mut except in KRAS codon 13 were considered, the classifier reached S+ of 94% / S- of 69%. We improved S- of the classifiers to 86%; 90%, and 86%, respectively by adding AREG and EREG RNA expression data. The most accurate classifier combined wt KRAS, wt BRAF, wt PIK3CA with mut in codon 13 and RNA expression of AREG and EREG and reached S+ of 94% / S- of 86%. Classification in corresponding primary tumors showed similar accuracy.

Conclusions: We developed a powerful classifier for all Dukes stages to predict response to CE with S+ of 94% and S- of 86%. In adjuvant setting the mut based classifier reaches S+ of 100% and S- of 68%; S- can be improved to 79% by adding AREG/EREG. This novel classifier has the potential to be used in the adjuvant and metastatic setting to improve pts selection for CE therapy.
Worse prognosis of KRAS C.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx).
Authors: Bruera Gemma , Cannita Katia , Di Giacomo Daniela , Lamy Aude , Troncone Giancarlo , Dal Mas Antonella , Coletti Gino , Frébourg Thierry , Sabourin Jean-Christophe , Tosi Mario , Ficorella Corrado , Ricevuto Enrico
Published: February 2017

521

Background: Bevacizumab (BEV) addition to doublet chemotherapy significantly increases efficacy without differentially affecting prognosis in KRAS wild-type (wt) and mutant (m) MCRC. Present study evaluates clinical outcome of BEV added to triplet chemotherapy, FIr-B/FOx (Bruera G et al, BMC Cancer 2010, 10:567), according to KRAS genotype.

Methods: MCRC patients (pts) were treated with first line FIr-B/FOx regimen including BEV (5 mg/kg, days 1,15) and triplet chemotherapy, weekly alternating irinotecan (160 mg/m2 days 1,15) or oxaliplatin (80 mg/m2, days 8, 22) associated to fluorouracil (900 mg/m2, days 1-2, 8-9, 15-16, 22-23); every 4 weeks. Tumoral samples were simultaneously screened for KRAS codon 12 and 13, and BRAF c.1799 T > A mutations by SNaPshot multiplex assay (Di Fiore F, Br J Cancer 2007;96(8):1166-1169) and/or direct sequencing. Activity and efficacy were evaluated and compared using log-rank test.

Results: Forty-five MCRC pts were evaluated: 25 KRAS wt (56%), 20 KRAS m (44%). After 30 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wt 88% (C.I. ± 14), 14 months, 38 months; KRAS m 80% (C.I. ± 19), 12 months, 21 months. PFS and OS were not significantly different. Among KRAS m pts, ORR, PFS and OS at 19 months median follow-up in c.35 G > A (13 pts) were 69% (C.I. ± 26), 9 months, 11 months, respectively. OS of c.35 G > A KRAS m was significantly worse compared to KRAS wt (p = 0.003) and to other than c.35 G > A mutant pts (p = 0.022).

Conclusions: First line FIr-B/FOx intensive regimen adding BEV to triplet chemotherapy can further increase activity and efficacy without significantly affecting different clinical outcome in KRAS wt and m MCRC pts. A significant interaction between the most prevalent c.35 G > A KRAS mutation and worse prognosis was observed, compared to KRAS wt pts and to other than c.35 G > A KRAS exon 2 mutations, depending from different biological aggressiveness and sensitivity to BEV addition to triplet chemotherapy.
A phase II, open-label study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy in patients (pts) with metastatic colorectal cancer (mCRC): CP12-0709/NCT00862784.
Authors: Garcia-Carbonero Rocio , Rivera Fernando , Maurel Juan , Ayoub Jean-Pierre M. , Moore Malcolm J. , Cervantes-Ruiperez Andres , Asmis Timothy R. , Schwartz Jonathan D. , Ballal Shaila , Tabernero Josep
Published: February 2017

533^

Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) are overexpressed in CRC and mediate angiogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 MAb that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In preclinical CRC models VEGFR-2 inhibition confers antitumor activity. RAM was administered with mFOLFOX-6 as 1st-line therapy (rx) in mCRC.

Methods: Eligible pts had mCRC with no prior chemo Rx (prior adjuvant rx was allowed), at least 1 measurable target lesion by RECIST v1.0, ECOG PS 0-1, and adequate organ function. Pts received RAM (8 mg/kg IV on D1), oxaliplatin (85 mg/m² IV on D1), folinic acid (400 mg/m² IV on D1), fluorouracil (5-FU, 400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46 hours on D1). Rx cycles were q2w and tumor assessments were q8w. Endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), safety, and pharmacokinetics/immunogenicity. Sample size was based on an improved median (medn) PFS from 8 to 11 months (m).

Results: 48 pts received therapy. All were white; 25 M/23 F; median age 60.5 y. ECOG PS was 0/1 in 30/18 pts. 42 pts (88%) had metastatic disease, with liver (79%) and lung (35%) as most frequent sites. 13 (27%) pts had liver-only mCRC. The most frequently observed RAM-related adverse events (AEs) included hypertension 46% (15% Grade [G] ≥3); diarrhea 31% (2% G≥3); and nausea and infusion-related reactions, each 19% (0% G≥3). 2 pts died on study due to acute MI or cardiopulmonary arrest. Medn PFS was 11.5 m (9-13 m 95% CI) with 1-yr PFS of 48% (32-62% 95% CI). ORR: 67% (52-80% 95% CI); disease control rate (DCR: CR+PR+SD): 94% (83-99% 95% CI; 5 pts had CR, 27 had PR and 13 had SD). Medn duration of response was 11.0 m (7-12 m 95% CI). One-year OS was 85% (72-93% 95% CI). As of 4/15/2011, 2 pts continued to receive rx, 20 had died and 28 (58.3%) remained alive.

Conclusions: RAM combined with mFOLFOX-6 was reasonably tolerated in pts with mCRC. Median PFS exceeds 11 m. PFS, ORR, and DCR are encouraging and favor investigation of this regimen and of RAM in mCRC.
Intermittent chemotherapy (CT) plus continuous or intermittent cetuximab (C) in the first-line treatment of advanced colorectal cancer (aCRC): Results of the two-arm phase II randomized MRC COIN-B trial.
Authors: Wasan Harpreet , Adams Richard A. , Wilson Richard H. , Pugh Cheryl , Fisher David , Madi Ayman , Sizer Bruce , Butler Rachel , Meade Angela M. , Maughan Tim
Published: February 2017

536^

Background: COIN-B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first-line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy.

Methods: Patients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Randomisation was: Arm D - continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E - OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure-Free Survival (FFS) at 10 months (mo) in KRAS-wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10-mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop-outs). Secondary outcome measures included safety, overall survival (OS) and toxicity.

Results: 169 KRAS-wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55-70); 92% PS 0-1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10-mo FFS rates were 48% vs 54% (one-sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1-20.3 and 8.6-23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5-6.2 and 2.5-8.9). In pre-planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1-8.1) in Arm D and 6.0 mo (IQR 2.9-10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented.

Conclusions: C was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.
Retrospective observational study: Bevacizumab (B) use and outcomes among metastatic colorectal cancer (mCRC) patients (pts) receiving care in the outpatient community in the United States.
Authors: Nadler Eric S. , Sail Kavita Rohidas , Chen Lei , Thompson Stephen F. , Kolodziej Michael A.
Published: February 2017

547

Background: This study assessed utilization and outcomes of B use in mCRC pts receiving 1st- (1L) and 2nd-line (2L) treatment (Tx) in this setting.

Methods: Data were abstracted primarily from US Oncology’s iKnowMed electronic medical record system. Multivariate Cox models were used for overall survival (OS) when testing differences between B and nonbiologic use. mCRC pts initiating 1L or 2L Tx from 1/1/07-6/30/09 were included. Cost of care was derived from outpatient claims data in US Oncology’s Claims Data Warehouse.

Results: 1795 pts were identified in 1L setting, 615 in 2L, and 323 in both 1L and 2L; 90% of 1L and 87% of 2L pts received combination Tx. Most received biologics (73% 1L, 65% 2L); among these, most included B (1131/1179 [96%] 1L, 312/345 [90%] 2L). B was commonly combined with FOLFOX (665/1131 [59%]) in 1L and FOLFIRI (135/312 [43%]) in 2L. Results for B use are described as 1L and 2L, respectively. Mean (median) numbers of cycles were 9.1 (7.0) and 7.0 (5.0), and 23% (301/1321) and 34% (120/348) received ≤3 cycles. Mean (median) durations of use were 141 (113) and 108 (75.5) days; average doses across all cycles for B were 5.5 mg/kg and 5.7 mg/kg. Consistent with the literature, 1L B was associated with a 23% reduction in risk of mortality vs nonbiologics (HR=0.77; CI: 0.60-0.98; P=0.036); however, 2L B was not associated with risk of mortality reduction (HR=0.87; CI: 0.62-1.22; P=0.44). With 1L B-containing regimens, median OS was 546.5 days in pts who continued B in 2L (n=269), and 569 days (P=0.11) in pts who did not (n=28); median costs for 2L B vs non-B were $5155 vs $3867 (P=0.068). 1L OS observed in this study was less than 1L OS reported in the BRITE registry (660 days; 95% CI: 21.9-24.4 months [doi: 10.1634/theoncologist.2009-0071]).

Conclusions: This study re-examines previously reported observations from the BRITE registry, but evaluates pts treated more recently and in both 1L and 2L settings. Our study did not show a significant survival advantage with prolonged use of B following progression. Further research is needed to confirm these findings. Research and editorial assistance was funded by sanofi-aventis U.S. LLC.
Multicenter phase Ib/II study of everolimus (RAD001) and tivozanib (AV-951) in patients with refractory, metastatic colorectal cancer.
Authors: Wolpin Brian M. , Ng Kimmie , Zhu Andrew X. , Abrams Thomas Adam , Enzinger Peter C. , McCleary Nadine , Meyerhardt Jeffrey A. , Schrag Deborah , Kwak Eunice Lee , Allen Jill N. , Bhargava Pankaj , Chan Jennifer A. , Goessling Wolfram , Blaszkowsky Lawrence Scott , Elliott Meaghan , Shellock Maria , Regan Eileen , Fuchs Charles S.
Published: February 2017

560

Background: Everolimus (E) is an oral inhibitor of mTOR. Tivozanib (T) is a highly potent, selective, oral inhibitor of VEGF receptors-1, -2, and -3. Preclinical data suggest antitumor activity for this combination in colorectal cancer. We therefore performed a multicenter Phase Ib trial of E + T in patients (pts) with any refractory gastrointestinal (GI) malignancy, followed by a Phase II trial of E + T in pts with refractory, metastatic colorectal cancer (mCRC).

Methods: Eligibility criteria: histologically confirmed, measurable disease; ECOG PS≤2; blood pressure ≤150/100; no venous thromboembolism within prior 6 months. Pts with mCRC must have received prior fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab and anti-EGFR antibody (if KRAS wt). E was administered once daily continuously. T was administered once daily for 3 out of every 4 weeks. The Phase Ib study in pts with any GI malignancy followed a standard 3+3 design with 3 dose levels: (1) E 5 mg/d + T 1 mg/d; (2) E 10 mg/d + T 1 mg/d; (3) E 10 mg/d + T 1.5 mg/d. The Phase II study in pts with mCRC was a non-randomized, one-stage design with a primary endpoint of progression-free survival.

Results: Between 02/10-12/10, 12 pts were enrolled to the Phase Ib study. Median age, 60 (39-81) years; male, 50%; ECOG PS 0/1/2, 42/58/0%; tumor types: esophagus 1, colorectal 11 pts. Dose limiting toxicities of grade 3 fatigue and grade 3 fatigue/ dehydration occurred in 2/6 pts on dose level 3. Grade 3/4 treatment-related adverse events in ≥10% of pts were dehydration, fatigue, headache, hyperglycemia, hypertension, and hypophosphatemia. The phase II study proceeded at the maximally tolerated dose (MTD) of E 10 mg/d and T 1 mg/d. Between 02/11-06/11, 40 pts with mCRC were enrolled to the phase II study. All but 1 pt received prior bevacizumab. Median age, 56 (35-81) years; male, 48%; ECOG PS 0/1/2, 45/53/2%. Treatment is ongoing.

Conclusions: Among pts with refractory GI malignancies, the combination of Everolimus + Tivozanib was well-tolerated with MTD of E 10 mg/d and T 1 mg/d. A phase II trial has completed enrollment using these doses of E + T in pts with refractory mCRC; safety and efficacy data will be available for presentation.
Targeted therapies for metastatic colorectal cancer (mCRC): A systematic review of cost-effectiveness (CE).
Authors: Bentley Tanya G. , Broder Michael Samuel , Das Lopamudra , Ortendahl Jesse , Su Yun , Wagner Samuel
Published: February 2017

583

Background: Currently three targeted agents are available for the treatment of mCRC. Making the right choice requires balancing efficacy, safety, quality of life, and, in cost-constrained systems, cost. This study aims to determine the most cost effective treatment in each line of therapy for mCRC through systematic review of published CE analyses (CEA).

Methods: Literature was searched in Medline, Cancerlit, EMBASE, Cochrane, CINAHL, BIOSIS, Web of Science, Tufts CEA registry, ASCO and ASCO GI for CEAs of the three mCRC targeted agents, cetuximab, bevacizumab, and panitumumab. Manuscripts from 2004-2011 and abstracts from 2009-2011, published in English and considering payer/societal perspectives were included. Incremental CE ratios (ICERs) were converted to US$ using 2010 purchasing power parity.

Results: 15 models from six countries were identified. Mean incremental costs per quality adjusted life year (QALY) and per life year (LY) gained are shown in the Table. All four models evaluating cetuximab in 1st line therapy, and only one of the six in 2nd+ line therapy, were done among biomarker selected KRAS wild type patients. Cetuximab’s cost effectiveness in 1st line therapy was driven by its ability to convert initially unresectable liver metastasis to resectable.

Conclusions: Lower ICERs appear to be associated with the use of a predictive biomarker and / or a sub patient population that can benefit the most from a treatment. With the KRAS biomarker and its potential curative benefit in patients with initially unresectable liver metastasis, cetuximab appears to be the most cost-effective targeted agent in 1st line mCRC treatment. In 2nd or later lines, direct CEA between the three agents in comparable biomarker selected patients are needed to determine the most cost effective agent.

[Table: see text]
Hepatic arterial embolization adopting polyvinyl alcohol microspheres preloaded with irinotecan versus systemic chemotherapy for hepatic metastases from colorectal cancer: A phase III clinical research trial of activity and quality of life.
Authors: Fiorentini Giammaria , Aliberti Camillo , Tilli Massimo , Coschiera Paolo , Mambrini Andrea , Giordani Paolo , Alessandroni Paolo , Benea Giorgio
Published: February 2017

587

Background: Patients with liver metastases (LM) from colorectal cancer (CRC) have a severe prognosis with the 5-year survival of 25% after radical resection; for not operable metastases the survival is poor. Embolization using polyvinil alcohol microspheres loaded with IRI 200 mgr (D) is a feasible procedure. FOLFIRI (CT) is active for the treatment of CRC. We planned this phase III study to assess survival as primary endpoint to increase median survival (MS) by 40% at 2-y (HR=0.72). QoL, responses, progression-free survival (PFS) and safety are secondary endpoints.

Methods: Between December 2006 and December 2008, 74 pts were randomized, 37 patients to D and 37 to CT. Two D patients had early progression and two CT patients refused. 70 cycles of D were administered in 35 pts, with a dose intensity (DI) of 99%, and 292 CT cycles were delivered to 35 pts with a DI of 90%.

Results: At a median follow up of 30 months ( 18-42) we reported (D vs CT): MS 48% vs 28%, Response Rate 70% vs 20%, Acute Toxicity 70% vs 20%, Late Toxicity 20% vs 80%, QoL improvement 65% vs 25%, Costs for each pt: 7,000 vs 24,000 euro.

Conclusions: D increased the 30-Months MS difference of 20% compared to CT. D improved responses, Performance Status and reduced costs. D reported higher immediate toxicity, mainly fever and abdominal pain, than CT. Late toxicity, mainly haematological, diarrhoea, asthenia and alopecia, was more common in CT. We conclude that D compared to CT increases survival and palliative results in patients with LM from CRC.
Relationship of the expression of IL-32 on NF-κB and p-p38 MAP kinase pathways in human esophageal cancer.
Authors: Yousif Nasser Ghaly , al-Amran Fadhil , Al-khirsani Hassan
Published: February 2017

59

Background: Esophageal cancer is the seventh leading cause of cancer death in males in the United States, and a strong link has been demonstrated between inflammation and esophageal cancer. Interleukin (IL)-32 is a recently described proinflammatory cytokine characterized by the induction of nuclear factor NF-κB activation, the p38 MAPK also plays an important role in key cellular processes related to inflammation and cancer. We investigated whether the IL-32 expression may be involved in esophageal carcinogenesis through modulates the activity of NF-κB and p- p38 MAPK.

Methods: Malignant esophageal and blood samples were obtained from 65 operable untreated patients, normal samples was obtained from 35 patients operated for other reasons as control. IL-32 expression, phosphorylated P38MAPK are visualized by immunohistochemistry, RT-PCR for IL-32 mRNA expression and for detected cytokines (TNF-α, IL-1 β, IL-6 and IL-8 ), NF-kB phosphorylation was analyzed by immunoblotting, ELISA for further detection IL-32 and cytokines concentration in the patients sera.

Results: IL-32 expression was increased in malignant esophageal samples compared with control (P = 0.01),and mostly in adenocarcinomas type (76.7%) and (21%) in squamous cell carcinomas. IL-32 expression detected at the mRNA level (P = 0.007 vs. control), and its correlated with NF-κB activation (P = 0.003), and up-regulation of phospho p38MAPK (P= 0.004), and also increased in the cytokines concentration compared with the control samples.

Conclusions: Understanding the pathway of IL-32 expression to stimulates the secretion cytokines via the activation of NF-κB and up-regulation of p- p38MAPK might be responsible in the esophageal carcinogenesis and used as tumor marker.
Metabolome analyses in human gastric cancer tissue using capillary electrophoresis time-of-flight mass spectrometry.
Authors: Terashima Masanori , Kusuhara Masatoshi , Kondo Junya , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Fujimori Tamaki , Yamamoto Hiroyuki , Ohashi Yoshiaki
Published: February 2017

61

Background: In order to explore carcinogenic and prognostic biomarkers for gastric cancer, genomic, transcriptomic and proteomic approach had been extensively investigated. However, little information is possible for metabolomics profiles in gastric cancer. As cancer cells demonstrates distinguishable growth pattern from normal cells, presence of specific metabolic pathway in cancer cells is expected. Therefore, we investigated the metabolme profiles of gastric cancer tissue by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS).

Methods: Twenty seven patients with gastric cancer underwent gastrectomy were enrolled in this study. Cancer tissue and adjacent non-cancerous tissue were obtained from surgically resected sample and immediately frozen. Frozen tissues were homogenized and then applied to CF-TOFMS.The metabolomics data by CE-TOFMS were analyzed using principal component analysis (PCA) in order to compare the metabolic profiling of the non cancerous and the cancer tissues. Correlation between metabolic profile and clinicopathologic factors were also investigated.

Results: A total of 245 metabolites were detected and quantified. In PCA, the first component separated the cancer tissue data from the non-cancerous tissue data. Metabolic data from cancer tissues showed severe heterogeneity. PCA based on the difference between cancer tissue and non-cancerous tissue revealed that metabolic profile of gastric cancer was classified into two groups. One cancer group (group 1) accumulated lactate and most amino acids excessively, and another group (group 2) didn’t. In group 1, the adenylate energy charge of the cancer tissues was maintained compared to that of the non-cancerous tissues.In comparison with clinicopathologic factors, only histological type demonstrated significant correlation with metabolic classification. Undifferentiated type was significantly predominant in group 2.

Conclusions: Gastric cancer was classified into two groups by quantitative metabolome profiling. As this classification significantly correlated with histological type, existence of specific metabolic pathway related to histological type is suggested.
Potential of surgery and chemotherapy in patients with second metastatic recurrence after R0-resection of colorectal liver metastases.
Authors: Homayounfar Kia , Bleckmann Annalen , Conradi Lena , Sprenger Thilo , Niessner Martin , Lorf Thomas , Becker Heinz , Ghadimi Michael B. , Liersch Torsten
Published: February 2017

644

Background: Surgical resection is the standard of care for resectable colorectal metastases (CRM). Preoperative chemotherapy allows assessment of tumorbiology and has been shown to convert approximately 30% of unresectable patients into secondary resectability. In patients with second metastatic recurrence (SMR), complete (R0) resection of all metastases seems to be accompanied with a survival benefit. The role of chemotherapy is unclear.

Methods: Between 01/2001 and 31/08/2011 R0-resection could be achieved in 178 patients with liver only CRM at our institution. 103 patients developed SMR 10.4 ± 8.9 months after R0-resection of hepatic CRM. Of these, 79 patients had perioperative 5FU-based chemotherapy for treatment of the primary tumor and/or first liver metastases. Median follow-up from diagnosis of SMR was 21 (range 1-80) months.

Results: SMR occurred in 80 patients at a single site (48x liver, 18x lung, 14x other) and in 23 patients at multiple sites (11x liver and lung, 7x including lung, 4x including liver, 1x other). 9 patients refused therapy and received best supportive care. 42 patients with single site recurrence were scheduled for primary surgery. R0-resection could be achieved in 26 patients (62%). 52 patients were treated with 8.1 ± 8 cycles of 5FU-based chemotherapy (5x 5FU/FS, 21x FOLFOX, 26x FOLFIRI) extended by the EGFR-antibody cetuximab (n=9) or the VEGF-antibody bevacizumab (n=18). 9 of these patients were scheduled for surgical exploration. R0-resection could be achieved in 5 patients with single site and 2 patients with multiple site recurrence. Morbidity and mortality rates for all operated patients were 16% and 0%, respectively. 5-years DFS rate for R0-resected patients was 20%. 5-years OS rate were 43% for R0-resected patients versus 11% for patients with R1/2 resection and palliative therapy (p<0.001).

Conclusions: Surgical resection of SMR offers a survival benefit and became possible even in 7 of 52 patients (13%) initially treated by chemotherapy. Therefore, all therapeutic options should be used in patients with SMR to achieve R0-resection of CRM.
Should lymph node retrieval be a surgical quality indicator in colon cancer?
Authors: Musselman Reilly Patrick , Xie Mingyang , McLaughlin Kelsey , Moloo Husein , Boushey Robin P , Auer Rebecca Ann C
Published: February 2017

648

Background: Adequate lymph node harvest is easily obtained and is necessary for proper staging of colorectal cancer, making it an attractive measure of surgical quality for policy makers. However, achieving an adequate lymph node harvest requires a multidisciplinary effort. The purpose of this study was to determine if it is appropriate to use this measure as a surgical quality indicator for individual surgeons.

Methods: The study was undertaken at a high volume center with standardized colon cancer specimen processes. The charts of 1,138 consecutive segmental colon cancer surgeries performed between 2002 and 2008 were retrospectively analyzed. The primary outcome was inadequate lymph node retrieval for colon cancer surgery defined by fewer than 12 lymph nodes on pathology. Predictor variables were based on patient, surgeon, pathology and tumor related factors. Univariate analysis was performed on all potential predictor variables, followed by multivariate logistic regression.

Results: 841 cases (69.0%) achieved adequate lymph node harvest, while 377 (31.0%) were inadequate. Factors on univariate analysis associated with inadequate lymph node harvest were specimen length (p<0.0001), tumor location (p<0.0001), and T-stage (0.0015), all of which remained significant multivariate logistic regression. The average specimen length differed by 3.6 cm between non-adequate and adequate specimens. When broken down by procedure, resection length did not vary significantly between high and low volume surgeons or between colorectal and non-colorectal surgeons. Furthermore when surgeons were ranked according to their success rate of >12 LN retrieval, there was no difference between surgeons in mean specimen length.

Conclusions: In a high-volume, tertiary care centre that uses standardized practices for specimen processing, 31% of cases yielded fewer than 12 lymph nodes. Factors relating to the patient and tumor were the primary predictors of a successful outcome and there was no association between surgeon-related factor and adequate LN retrieval. Caution should be used when considering LN harvest as a surgical quality indicator for individual surgeons.
Dexamethasone as a means for controlling vascular pain caused by the administration of oxaliplatin via the peripheral vein and also for controlling oxaliplatin-induced hypersensitivity reactions.
Authors: Yoshida Yoichiro , Hoshino Seiichiro , Aisu Naoya , Shiwaku Hironari , Beppu Richiko , Tanimura Syu , Yamashita Yuichi
Published: February 2017

662

Background: With the recent development of XELOX therapy involving oral administration of drug preparations, etc., implantation of a CV port can be now avoided. However, vascular pain (pain in the peripheral veins) occasionally requires switching of the drip infusion route during XELOX therapy. Some investigators reported that addition of steroids to oxaliplatin drip infusion is useful in controlling vascular pain. However, the pharmacological use of steroids can make oxaliplatin unstable due to the elevation of pH; further, the effectiveness of oxaliplatin in this therapy is unknown because of lack of published data. This study was undertaken to evaluate the effectiveness of dexamethasone (DEX) in infusion solution containing oxaliplatin for controlling vascular pain caused by the administration of oxaliplatin via the peripheral vein.

Methods: The study included 47 patients (33 males and 14 females; median age, 64) who received XELOX + bevacizumab for metastatic colorectal cancer without implantation of a CV port. In all the patients, oxaliplatin (130 mg/m2) was administered in combination with DEX (6.6 mg) via the peripheral vein.

Results: Vascular pain developed in 34 patients (72.3%), but it was transient. In only 1 of the 34 patients, the drip infusion route had to be switched to the opposite side because of vascular pain. No patients required CV port implantation. Grade 3 or higher hemotoxicity was noted in 14.9% of the patients, and grade 3 or higher nonhematological toxicity was noted in 21.2% of the patients. The response rate was 61.7%. Among 47 patients, no patients experienced hypersensitivity reactions to oxaliplatin.

Conclusions: Addition of DEX to oxaliplatin drip infusion controlled vascular pain caused by the administration of oxaliplatin via the peripheral vein. The response rate to this therapy combined with the use of DEX suggests that DEX probably does not exert adverse effects on the therapy, ie, it does not affect the stability of oxaliplatin by elevating the pH. Furthermore, coinfusion of DEX to oxaliplatin may be a useful preventive method for oxaliplatin-induced hypersensitivity.