bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aflibercept in combination with FOLFIRI for the second-line treatment of patients with metastatic colorectal cancer: First interim safety data from AFEQT trial.
Authors: Ben Abdelghani Meher , Borg Christophe , Dourthe Louis-Marie , Deplanque Gael , Taïeb Julien , Metges Jean-Philippe , Laplaige Philippe , Lotz Veronique , Amrate Amele , Lledo Gérard 
Published: February 2017

661 Background: In the randomized phase 3 VELOUR trial, aflibercept + FOLFIRI demonstrated a statistically significant overall survival benefit compared with FOLFIRI alone in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-based regimen. Evidence from the VELOUR trial supported the initiation of a French clinical trial; AFEQT [NCT01670721] to capture utility values from QoL instruments and collect safety data from a target population similar to that in VELOUR. Interim data collected by French investigators are reported. Methods: AFEQT is single-arm, open-label trial evaluating safety and health-related QoL of aflibercept in mCRC pts previously treated with an oxaliplatin-based regimen. Estimated total enrollment is 200 mCRC pts. Eligible pts received aflibercept (4 mg/kg) q2wks on day 1 of each cycle followed by FOLFIRI up to disease progression, unacceptable toxicity, death, or investigator/patient decision, whichever occurred first. FOLFIRI starting dose and subsequent additional dose modifications were at the discretion of the treating physician. Safety assessments followed each cycle and continued until 30 days after last drug administration. The percentage of pts with grade 3/4 adverse events (G3/4 AEs) in the safety population of AFEQT was compared with that of VELOUR. Results: At data cut-off, the safety population comprised 123 pts with at least 1 completed cycle of treatment. Median age of pts was 64.6 vs. 61 years in VELOUR. At least 1 G3/4 AE was experienced by 67.5% of pts vs. 83.5% in VELOUR. Most reported G3/4 AEs were G3. There were no reports of G4 hypertension or diarrhea. Additional data will be reported during the meeting. Conclusions: In VELOUR, AEs occurred early in treatment, were often of single occurrence, generally reversible, and consistent with AEs commonly seen by oncologists. Interim safety analysis from AFEQT did not identify any new safety signal. Clinical trial information: NCT01670721. [Table: see text]
Association of modern era adjuvant chemotherapy with improved survival in patients with stage II colon cancer.
Authors: Casadaban Leigh , Villenes Dana , Rauscher Garth , Aklilu Mebea , Maker Ajay V. 
Published: February 2017

671 Background: Patients are often selected for adjuvant therapy after resection of stage II colon cancer based on the presence of poor risk factors. However, the survival advantage of chemotherapy in this population is unclear and there remains variation in clinical practice. Methods: The National Cancer Data Base was analyzed for colon cancer patients treated 1998-2006. The primary outcome was OS between patients who did or did not receive adjuvant chemotherapy. Additional stratification variables included high-risk disease features, age, multi-agent chemotherapy, and diagnosis after 2004 when oxaliplatin was approved for adjuvant therapy. Demographic and disease information was compared using the Pearson Chi-squared test and binary logistic regression, effect size with Cramer's V/Phi for categorical variables, and survival data with Cox regression. Propensity score weighting was utilized to account for the possibility of selection bias. Results: Of 1,078,091 patients with colorectal cancer, 153,110 stage II colon cancer patients met inclusion criteria. Mean age was 72, 46% were male, 84% stage IIA (AJCC 6thed.), 9% stage IIB, and 20% received adjuvant chemotherapy. Predictors of receiving treatment included age<65, male gender, community treatment facility, geographical location, non-Medicare insurance, education level, and diagnosis before 2004. All patient sub-groups analyzed experienced improved OS with adjuvant chemotherapy regardless of the number of high-risk features, age, multi-agent chemotherapy, or adjustment for covariates. Median OS was 13.2 years in the chemotherapy group and 7.0 years in the no-chemotherapy group (p< 0.001). Median and 5-year OS was improved in both high and low-risk patients who received chemotherapy compared to those who did not with a median follow-up >5 years. Conclusions: This large-scale study with long-term follow-up demonstrated that adjuvant chemotherapy was associated with a clinically relevant improvement in OS regardless of treatment regimen, patient age, or high-risk features in patients with resected stage II colon cancer. The results of this retrospective analysis warrant further investigation in prospective trials.
Adjuvant treatment for resected rectal cancer: Effect of postoperative oxaliplatin added to 5-FU in the neoadjuvant era.
Authors: Garlipp Benjamin , Stuebs Patrick , Lippert Hans , Ridwelski Karsten , Ptok Henry , Gastinger Ingo , Otto Ronny , Bruns Christiane J. 
Published: February 2017

672 Background: Oxaliplatin (Ox) added to postoperative 5-fluorouracil (5FU) based adjuvant treatment has shown a survival benefit in colon cancer. For rectal cancer, the impact of Ox on survival has almost exclusively been tested in studies using 5FU +/- Ox both as a component of preoperative chemoradiotherapy (CRT) and as adjuvant treatment. Only one study (NCT00807911) investigated adjuvant 5FU +/- Ox in patients undergoing preop 5FU based CRT without Ox. Thus, the evidence for the benefit of adding Ox to adjuvant 5FU in patients treated with preop 5FU based CRT is limited. Methods: Data from the prospective German multicenter Quality Assurance in Rectal Cancer observational trial involving more than 300 hospitals of all levels of care throughout Germany were retrospectively analyzed. Patients undergoing R0 total mesorectal excision (TME) for rectal cancer following neoadjuvant 5FU based treatment without oxaliplatin between 01/01/2008 and 12/31/2010 were included. Disease-free survival (DFS) in patients receiving adjuvant treatment with or without Ox was compared using the Kaplan Meier method. The impact of adjuvant treatment with 5FU with or without Ox on DFS was investigated in a Cox regression analysis including open vs. laparoscopic approach, pT stage, pN stage, tumor grading, TME quality grade, and presence of anastomotic leakage as potential confounding factors. Results: The entire data set included 1,861 patients. Data for all variables investigated were available for 599 patients of whom 512 (85%) and 89 (15%) received 5FU based adjuvant treatment without and with Ox, respectively. Mean DFS was not different in patients receiving 5FU only vs. 5FU with Ox (p=0.103). Cox regression analysis revealed no significant impact of adding Ox to adjuvant 5FU on DFS. Of all factors analyzed, only pN2 (vs. pN0) status had an independent adverse effect on DFS (Hazard ratio 4.22, p<0.001). Conclusions: These data indicate that adjuvant Ox added to 5FU does not provide a DFS benefit in rectal cancer patients treated with preoperative 5FU based CRT under routine care conditions. Rectal cancer patients may be different from patients with colon cancer with respect to benefit from adjuvant Ox.
A cost model of capecitabine versus continuous infusional 5-fluorouracil (CI5FU) as chemosensitization during long course radiotherapy in the neoadjuvant treatment of rectal cancer: From the perspective of the Australian health care system.
Authors: Paterson Robin John , Randall Kelly , Day Fiona 
Published: February 2017

688 Background: Recent phase III clinical trials have shown that the use of capecitabine with long course radiotherapy in the neoadjuvant treatment of rectal cancer provides equivalent outcomes to the traditionally used CI5FU. In the Australian health system the dispensed price of capecitabine is higher; however CI5FU administration requires a peripherally inserted central catheter (PICC). This analysis was designed to test the comparative cost of capecitabine over CI5FU from the perspective of the Australian healthcare system. Methods: We determined fully itemised direct treatment costs for the administration of neoadjuvant long course chemoradiotherapy with each of capecitabine and CI5FU. A decision analytic model was then used to compare potential clinical adverse events with the respective agents. Clinical probabilities were derived from published studies and the management of adverse events costed using Australian refined diagnosis-related group (AR-DRG) coding. The results of the decision analytic model were integrated with the drug administration costs to produce an inclusive discriminating cost for capecitabine versus CI5FU. Results: The total cost to the Australian healthcare system for the administration of CI5FU was $2,110 per patient, compared with $1,170 for capecitabine. The costs of managing treatment complications were similar: mean $174 per patient for CI5FU and $72 for capecitabine. The integrated discriminating cost difference was a mean saving of $1,042 per patient with prescription of capecitabine. The presented base-case model utilised higher capecitabine costs where input data could vary, and hence in all sensitivity analyses capecitabine continued to demonstrate cost savings (minimum $286 and maximum $1,975 per patient) over CI5FU. Conclusions: Capecitabine is a cost effective alternative to CI5FU. Considering also the expected lower indirect costs with oral therapy, use of capecitabine in chemoradiotherapy for rectal cancer is economically superior.
Differences of mutation of helicobacter pylori cagA gene isolated from duodenal ulcer and gastric cancer.
Authors: Kim Sung Soo , Cheung Dae Young , Park Soo-Heon 
Published: February 2017

69 Background: H. pylori is the pathogen of both duodenal ulcer and gastric carcinoma. However, they are markedly different in terms of its physiologic and pathologic basis. CagA is 120-145-kDa protein of H. pylori and located one end of Cag PAI encoding components of type IV secretion system. H. pylori expressing CagA are associated with development of atrophic gastritis, peptic ulcer, and gastric carcinoma. This study was aimed to examine the differences of cagA mutations of H. pylori isolated from duodenal ulcer and gastric carcinoma. Methods: Isolated H. pylori from 29 patients with gastric carcinoma and 31 patients with duodenal ulcer were compared the frequency of mutations after cloning of cagA of H. pylori. Results: Even there were diverse mutations scattered on whole sequence of cagA, mutations were more frequent in amino acid sequence 200-400 and 850-1100. Amino acid loci G311, D371, M393, T899, and S1068 were mutated in more than half of patients regardless of diseases. The mutations of CagA in C-terminal area, especially Q889, T899, R952, A968, R997, K1034, Q1067, and S1068, were 20% or more frequent in H. pylorifrom duodenal ulcer than those from gastric carcinoma. EPIYA type was not different between the duodenal ulcer and gastric carcinoma. Conclusions: These results suggest that the mutations of cagA of H. pylori, especially in C-terminus are distinguishable between duodenal ulcer and gastric carcinoma.
Trends in the design and interpretation of metastatic colorectal cancer phase III clinical trials.
Authors: Parimi Sunil , Raissouni Soundouss , Lin Yongtao , Monzon Jose Gerard , Tang Patricia A. , Tam Vincent Channing 
Published: February 2017

692 Background: Increasing use of subsequent lines of therapy and crossover in phase III randomized clinical trials (P3 RCTs) has shifted how we perceive the effectiveness of treatments for metastatic colorectal cancer (mCRC). This study aims to characterize the evolution of P3 RCTs in mCRC with respect to clinical trial design and result interpretation. Methods: Abstracts of P3 RCTs of systemic therapy for mCRC conducted between 1980 and 2014 were identified by searching PubMed, Medline, and ASCO abstracts. Data regarding trial design, agent(s) investigated, primary endpoint, secondary endpoint(s), primary endpoint significance and interpretation of the study results (conclusions) were extracted. Results: A total of 422 trials were identified by the search strategy, and 132 eligible trials were included. Over time the sample size of P3 RCTs in mCRC has been increasing and there has been a steady increase in trials studying targeted therapy (see table below for detailed results by decade). A trend towards a smaller percentage of P3 RCTs sponsored by co-operative groups has been observed in recent decades. The most common primary endpoint was overall survival (OS) which was used in 35% of the trials. A decreasing trend in the use of OS was observed since the 1990s. Other common primary endpoints include: progression-free survival (PFS) in 28% and response rate (RR) in 20% of the P3 RCTs. The primary endpoint was met in 45% of the trials. There was discordance between the primary endpoint significance and the authors’ conclusions in 14% of the trials. Conclusions: The design and interpretation of P3 RCTs for mCRC has changed over time from 1980 to present. The use of OS as the primary endpoint is decreasing, while the use of PFS is increasing. [Table: see text]
Exploratory RAS analysis of the phase Ib/II 20060447 trial of rilotumumab (R) or ganitumab (G) plus panitumumab (pmab) versus pmab alone in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Eng Cathy , Van Cutsem Eric , Nowara Elzbieta , Swieboda-Sadlej Anna , Tebbutt Niall C. , Mitchell Edith P. , Davidenko Irina , Lee Oliver , Oliner Kelly Smith , Schupp Marco , Loh Elwyn , Sidhu Roger , Tabernero Josep 
Published: February 2017

694 Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evaluable for RAS. Of 92 evaluable pts, 79 (86%) were WT RAS (WT in KRAS and NRAS exons 2, 3, and 4) and 13 (14%) had RAS mutations beyond KRAS exon 2 (mutant in any KRAS exon 3 or 4 or NRAS exon 2, 3, or 4). None of the pts with RAS mutations had an objective response (Table). Of 93 pts evaluable for BRAF, 7 (8%) had V600E mutations (all 7 were WT RAS). Two pts with BRAF V600E tumors had a partial response and were in the pmab+R arm (n=3). No new safety signals were identified. Conclusions: In this small, retrospective study, ORR, PFS and OS were similar between the arms of R or G plus pmab vs pmab alone in pts with WT RAS mCRC tumors. Our findings indicate that RAS mutations beyond KRAS exon 2 impact ORR, PFS, and OS. Clinical trial information: NCT00788957. [Table: see text]
Impact of perineural and lymphovascular invasion on oncological outcomes in rectal cancer treated with neoadjuvant chemoradiotherapy and surgery.
Authors: Cienfuegos Javier A. , Rotellar Fernando , Baixauli Jorge , Beorlegui Carmen , Sola Iosu , Arbea Leire , Pastor Carlos , Arredondo Jorge , Hernandez-Lizoain Jose Luis 
Published: February 2017

695 Background: The prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery. Methods: A total of 324 patients with LARC treated with CRT were operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification, and the presence of PLVI was studied histologically. Results: At a median follow-up of 79.0 months (range 3–250 months), a total of 80 patients (24.7%) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2% and 74.9% respectively. The 5- and 10-year disease-free survival (DFS) was 75.1% and 71.4%, respectively. A significant correlation was found between the TRG and survival (log rank, p<0.001). The 10-year OS and DFS was 32.7% and 31.8% for grade 1; 63.8% and 58.6% for grade 2; 75.0% and 70.4% for grade 3; 90.4% and 88.4% for grade 3+, and 96.0% and 97.1% for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, TRG was an independent prognostic factor for OS and DFS. Conclusions: The presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.
The association of baseline anxiety and depression with overall survival (OS) in colorectal cancer (CRC).
Authors: Cheung Pierre Y. , Liu Tian Yang Darren , Kim Jason D. , Cheung Winson Y. 
Published: February 2017

706 Background: Patient-reported measures such as psychosocial wellbeing and quality of life have been reported to correlate with cancer survival, but the specific factors within these constructs that associate with outcomes remains poorly defined. Our aim was to examine the effect of baseline anxiety and depression on OS in a population-based cohort of CRC patients. Methods: Patients diagnosed with CRC in 2008, referred to any 1 of 5 regional cancer centers in British Columbia, and who completed a baseline questionnaire to evaluate anxiety and depression were reviewed. We developed a scoring system based on these patient-reported survey data to characterize intensity and subsequently categorized patients as having no, mild, moderate or severe anxiety and/or depression. Vital statistics were captured by medical records. Unadjusted Kaplan-Meier methods and multivariate Cox regression models that controlled for additional socio-demographic and clinical characteristics were constructed to correlate anxiety and depression with OS. Results: A total of 449 patients were included: median age was 66 years (range 26-92), 52% were men, and 69% were white. A significant proportion of respondents reported anxiety (58%) or depression (45%) at baseline. Among them, the majority indicated their anxiety and depressive symptoms were severe (43% and 43%, respectively). Women and those who were single or unmarried were more likely to have anxiety and depression (p<0.001 and p=0.02, respectively). In unadjusted analyses, we observed a trend where increased severity of anxiety (p=0.07) and depression (p=0.04) correlated with worse outcomes. In Cox regression that considered other prognostic factors, however, this observation failed to persist, and neither anxiety nor depression associated with OS (Table). Conclusions: The impact of psychosocial wellbeing and quality of life on CRC outcomes that have been previously described in the literature are unlikely to be mediated through baseline anxiety or depression. [Table: see text]
Identifying variables that predict poor tumor biology and suboptimal outcomes in patients treated with cytoreduction and HIPEC.
Authors: Singla Smit , Francescutti Valerie , Kane John Michael , Skitzki Joseph J. 
Published: February 2017

709 Background: Cytoreduction with HIPEC has improved survival in select group of patients with peritoneal carcinomatosis. Despite rigorous selection criteria, some patients invariably perform worse than others and are presumed to conceal poor tumor biology. Methods: A single institution analysis of all patients presenting with peritoneal carcinomatosis between 2003 and 2014. All patients who underwent CRS with HIPEC were included in the analyses. Clinical variables deemed high risk for poor outcome were categorized as ‘poor tumor biology’ and analyzed using the multivariate association for survival outcomes. Results: Based on pre-defined criteria, 160 patients (M: 68, F: 92; median age, 53 years) were identified and included in this study. The most common site of tumor origin was appendix (n=73, 45.6%), and the most common histology subtype was adenocarcinoma (n=91, 56.9%). Patients presenting with ascites (n=39, 24.3%, p<0.001) and perforation (n=18, 11.2%, p=0.036) performed poorly, while age (young versus old), gender and the timing of surgery from diagnosis did not affect survival outcomes (p>0.05). Patients who received pre-operative chemotherapy (n=77, 48%, p=0.007), complete cytoreduction (n=115, 71.9%, p=0.02) and fewer number of gastrointestinal anastomoses (=<1, p=0.005) during surgery performed better; however, patients who developed intra-abdominal abscess, anastomotic leak, fistula and bowel obstruction in the immediate peri-operative period (n=30, 18.8%, p<0.001) saw significant decline in survival outcome. The median overall survival and progression free survival in our patient cohort were 68.0 months (CI, 46.8-NR) and 19.3 months (CI, 14.7-37.4), respectively; but patients with colorectal adenocarcinoma, ascites, perforation and bowel complications performed poorly and were assumed to harbor poor biology. Conclusions: A thorough understanding of the presenting symptoms and peri-operative clinical variables can identify patients with poor tumor biology. These patients are unlikely to have significant improvement in outcome, and cytoreduction with HIPEC can be considered palliative in these patients.
Effect of TP53 mutation status on survival in the MAGIC trial.
Authors: Smyth Elizabeth Catherine , Hulkki Wilson Sanna , Nankivell Matthew Guy , Gonzalez de Castro David , Wotherspoon Andrew , Okines Alicia Frances Clare , Langley Ruth E , Stenning Sally Patricia , Cunningham David 
Published: February 2017

71 Background: In oesophagogastric cancer TP53 mutation may be prognostic and/or predict for chemoresistance, however available data are conflicting. We hypothesised that TP53 status would impact on survival for patients (pts) randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: Genomic DNA FFPE tissue sections were extracted with QIAmp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Mutations in exons 4-9 were screened for by fluorescent PCR -amplification of genomic DNA, followed by Capillary Electrophoresis-Single Strand Conformational Analysis (CE-SSCA). Mutations were characterised by bi -directional Sanger sequencing analysis performed on an independent PCR -reaction and the sequencing results were compared to the reference sequences in the COSMIC database. TP53 status was correlated with demographics and survival. Results: TP53 results were available on 154 pts (50% of pts with available DNA). The remainder failed CE-SSCA due to degraded DNA. Pts with/without TP53 data had similar demographics and survival. TP53 mutation was detected in 51/154 (33%) samples. Exon 4, 5, 6, 7 and 8 mutations occurred in 4%, 42%, 8%, 36% and 10% of specimens with a TP53 result. Pts with TP53 mutations were more likely to have an oesophageal or junctional tumor (vs. gastric) than TP53 wild type (WT) pts (38% vs. 17% respectively p = 0.016). Survival from surgery was comparable for pts with mutant and WT TP53 tumors in both arms of the trial (See Table). P-value for interaction between treatment group and TP53 status was 0.776, indicating no interaction was present. Conclusions: In the MAGIC trial, TP53 mutation status was not prognostic, and did not predict for lack of benefit from chemotherapy. Further study is required in order to evaluate the effect of differing TP53 mutations on treatment and survival. [Table: see text]