bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perioperative chemotherapy with bevacizumab (BV) for liver metastases (LM) in colorectal cancer (CRC): McGill University pilot study
Authors: Bouganim N. , Kavan P. , Eid M. , Metrakos P. , Chaudhury P. , Batist G. 
Published: August 2020

e15027 Background: Colorectal liver metastases treated with perioperative chemotherapy were previously shown to increase progression free survival. Given the survival benefit of bevacizumab in metastatic CRC, the aim of this study was to assess the efficacy and safety of bevacizumab based chemotherapy in the perioperative setting. Methods: In this single arm prospective pilot study, patients with resectable LM eligible to receive perioperative BV and chemotherapy were included. Kaplan Meier survival analysis was used to calculate overall survival and progression free survival. Results: A total of 60 patients were recruited, 41 male, with an average age of 55. Forty-three patients had synchronous LM. All but seven patients received pre and post-operative BV-based chemotherapy (34/60 oxaliplatin based, 22/60 CPT-11 based and 4/60 CPT-11 and oxaliplatin based). All patients underwent hepatectomy 6–8 weeks post last dose of BV. Overall response rate was 80% (48/60), 4pt with stable diseaase; 10% had a complete pathological response and 27% had no evidence of disease post hepatectomy with a median follow up of 33 months.8 patients progressed prior to surgery. Overall survival (OS) rates at 12, 24, 36 and 48 months were: 100%, 86%, 74% and 66% respectively and 5 year median survival of 55%. Progression free survival (PFS) was 14 months. Subgroup analysis of the data according to the chemotherapy pts received showed that PFS in the CPT-11 and the oxaliplatin arm were 13 and 15 months respectively. Most of the adverse events recorded were associated with the post-operative period and included wound healing (8pts), infections (2pts) and thromboemblic (6pts) disease. No sudden deaths or bowel perforations were reported. Conclusions: Bevacizumab-containing chemotherapy regimens in the peri-operative setting is effective in patients with colorectal liver metastases. Our 80% response rate and 10% complete pathological response is one of the highest reported and warrants further investigation in phase III trials. [Table: see text]
Phase II trial of imatinib, bevacizumab and cetuximab plus modified FOLFOX-6 in advanced untreated colorectal cancer
Authors: Sobrero A. F. , Bennicelli E. , Pessino A. , Guglielmi A. , Mammoliti S. , Caprioni F. , Fornarini G. , Comandini D. , Sciallero S. , Ansaldi F. 
Published: August 2020

e15030 Background: Imatinib inhibits PDGFR interfering with pericytes, the structural support to newly formed tumor blood vessels. It may thus synergize with bevacizumab. Microenvironment and tumor targeted agents along with chemotherapy could be a promising add-on approach. Methods: cetuximab 500 mg/m2, bevacizumab 5 mg/kg and modified FOLFOX-6 were given i.v. on day 1 and repeated every 2 weeks. Imatinib 400 mg/day per os was given continuously. Due to the cost and potential toxicity of the combination, the endpoint for this phase II study was very ambitious: at least 25% of complete response (medically or surgically achieved), lasting a minimum of 12 months in advanced untreated colorectal cancer patients with clearly unresectable disease. Results: Of 26 patients (16 with 1 site of disease), 17 completed the first 4 months of treatment according to the protocol, while 9 had to discontinue one biologic drug due to side effects (5 cetuximab, 3 imatinib and 1 bevacizumab). Grade 3–4 toxicity: diarrhea 12%, neutropenia 24%, skin rash 24%, hypersensitivity reactions 16%, asthenia 8%, neuro 8%. All patients were evaluable for response. Eleven responses ( 1 CR and 10 PR), 13 SD and 2 PD were observed, corresponding to 42% RR ( 95% CI = 23–61). The minimum follow up is 12 months; median PFS is 10 months. One patient among responders underwent radiofrequency ablation and 17 patients underwent surgery: 8 R-0, 3 R-1, 5 R-2 and one exploratory laparotomy. Major post surgical complications occurred in 5/17 patients. No evidence of macroscopic disease after the entire treatment plan was obtained in 13/26 patients: 12 surgical and 1 medical CR. Seven/13 were disease free at 6 months, but only 3 were still disease free at 12 months. ERCC1, ERCC2/XDP, GSTP1,TS,EGF, COX2, CYCLIN D, FCgR polymorphisms and K-RAS mutations were evaluated on all 26 patients, but no correlations were found with clinical outcome. Conclusions: The triple combination of biologics with modified FOLFOX-6 is feasible and tolerable as initial aggressive treatment. The primary endpoint of the study was not met . In fact the activity, 42% RR, was not outstanding and the high resectability rate, 69%, is misleading in the light of the short duration of the surgically induced CR. [Table: see text]
Adjuvant chemotherapy for resected stage II and III colon cancer: Comparison of widely used two prognostic calculators
Authors: Bardia A. , Loprinzi C. , Grothey A. , Nelson G. , Alberts S. , Patiyil S. , Thome S. , Gill S. , Sargent D. 
Published: August 2020

e15031 Background: Two web based prognostic calculators, Adjuvant! and Numeracy (JCO 22:1797–1806, 2004) are widely used to provide individual patient outcome predictions to aid decisions regarding adjuvant therapy for colon cancer. The comparability of these tools has not been studied yet. The aim of this project was to assess whether the Numeracy and Adjuvant! Colon cancer prognostic tools produced similar results for patients with resected stage II and III colon cancer based on a set of hypothetical patients. Methods: All possible hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were applied to three post- surgical therapy choices: observation, 5-FU (5-fluorouracil), or FOLFOX (5-FU, leucovorin and oxaliplatin). Predictions for these hypothetical scenarios (N= 192 for males and 192 for females) were also entered into the Adjuvant! Program. Predicted relapse free survival (RFS) and overall survival (OS) were obtained using both calculators. Wilcoxon signed rank tests were used to compare the numerical predictions between the calculators for each outcome. Results: In the majority of the 384 hypothetical patient scenarios, predictions for RFS and OS from Adjuvant! were statistically significantly higher than from Numeracy (p value < 0.05), except for age≥70 for FOLFOX, and the number of positive nodes of 0 and 1–4 using FOLFOX, among males. The net estimate of benefit for RFS and OS for 5-FU over surgery, obtained from Adjuvant! and Numeracy, were similar (for both males and females), but the benefit in RFS and OS for FOLFOX over 5-FU obtained from Adjuvant! was significantly lower than the estimate obtained from Numeracy (p value < 0.05). Conclusions: Based on a hypothetical set of patients with resected stage II and III colon cancer, the estimated benefit in RFS and OS of FOLFOX over 5-FU based chemotherapy is lower in Adjuvant! than in the Numeracy tool (but benefit for 5-FU over surgery alone is similar). Further studies are needed to clarify the discrepancy and to assess which of these tools most accurately reflects actual patient outcome. No significant financial relationships to disclose.
Prognostic significance of VDR, DKK-1, and DKK-4 expression in colorectal cancer
Authors: Posey J. A. , Koya S. , Katkoori V. R. , Davis D. E. , Manne U. 
Published: August 2020

e15047 Introduction: Inactivation of the vitamin D receptor (VDR) and up-regulation of its down-stream molecules, Dickkopf-1 (DKK-1) and DKK-4 are implicated in the aggressive progression of colorectal adenocarcinomas (CRC). In this study, the expression of these molecules was evaluated in sporadic CRCs, and their expression levels were assessed for correlation with patient prognosis. Methods: By the qRT-PCR, 98 CRCs and matching normal tissues were analyzed for expression of VDR, DKK-1, and DKK-4 at the mRNA level. These levels were normalized to b-actin expression and calculated as ratios of copy numbers. The expression levels were assessed for correlation with clinicopathological features and for their prognostic importance. The survival probabilities were estimated by the Kaplan-Meier method. Results: VDR expression was 1.5 times lower in CRCs (53 of 98, 54%) than in their corresponding normal tissues. Expression of DKK-1 was found in 51 of 98 (52%) of the CRCs and in 29 of 98 (29%) of the normal tissues. Expression of DKK-4 was found in only 14 of 98 (14%) of the CRCs and in none of the normal tissues. VDR expression was 2.0 fold lower in tumors that exhibited metastasis, and poor differentiation and in large tumors ( > 5) cm as compared to tumors without metastasis, well or moderately differentiated tumors and tumors of small size (< 5 cm), respectively. In contrast, increased (3-fold) expression of DKK-1 and DKK-4 was observed in tumors with distant and/or nodal metastases as compared to tumors without such metastases. Expression of DKK-1 was higher in tumors with poor differentiation and in large tumors. There was an inverse relationship between VDR and DKK-4 expression. Survival analyses suggested that CRCs expressing DKK-1 (log rank, P = 0.046) and those with decreased or lack of expression of VDR (log rank, P = 0.043) were associated with poor patient survival. There was, however, no prognostic value for DKK-4 expression (log rank P=0.624). Conclusions: These findings suggest that, for CRCs, increased expression of DKK-1 and reduced or lack of expression of VDR, are associated with aggressiveness and with a poor prognosis for patients. These results provide evidence augmenting the VDR-DKK- pathway may represent a rational therapeutic strategy in colorectal carcinoma. No significant financial relationships to disclose.
Development of an assay for KRAS mutation as a predictive marker for cetuximab in colorectal cancer
Authors: Yokota T. , Muro K. , Shibata N. , Ura T. , Takahari D. , Shitara K. , Yatabe Y. 
Published: August 2020

e15048 Background: The activating KRAS mutation is an important predictive marker for anti-EGFR therapy against colorectal cancer (CRC), although valid assays using pathological specimens have not been yet established. We present a rapid, sensitive assay for KRAS genotyping using small biopsy specimens. Methods: We used Cycleave PCR to detect the KRAS mutation in CRC with a chimeric DNA-RNA-DNA probe labeled with fluorescent dye and quencher, with results obtained within 4 hours. Template DNA was extracted from formalin-fixed, paraffin-embedded specimens, which are surgically resected or biopsied in clinical practice. Results: To evaluate Cycleave PCR accuracy for detecting the KRAS mutation, we compared with results of reverse transcriptase-PCR-coupled direct sequencing (RT-PCR-DS) of metastatic lung tumor specimens from CRC patients. KRAS mutations were present in 40 (43%) of 94 patients, including 28 (30%) and 8 (9%) in codon 12 and codon 13 mutations, respectively. Concordant results between Cycleave PCR and RT-PCR-DS in KRAS codon 12 and 13 were found in 35/36 (97%) and 23/23 (100%), respectively. We also applied this method to surgical specimens in clinical practice. Although 8 from 73 patients (11%) could not be evaluated with Cycleave PCR, corresponding biopsy specimens could be used alternatively. Because biopsy specimens were fixed by formalin for a shorter period, fixation of surgical specimens for longer time may have contributed to PCR failure. Indeed, over- fixation by formalin impaired PCR amplification of KRAS in time-dependently. Furthermore, results of 4 randomly selected biopsy specimens using Cycleave PCR were consistent with those of surgical specimens. Conclusions: Cycleave PCR even using biopsy specimens is accurate, rapid, and useful to detect KRAS mutations in CRC patients. This study also called attention to specimen selection, as over-fixation by formalin may lead to failure of the gene examination due to template DNA fragmentation. This method can be applied to examine BRAF genotyping as well as KRAS. KRAS/BRAF genotyping by Cycleave PCR leads to individualized therapy using cetuximab for CRC patients. No significant financial relationships to disclose.
High- versus low-dose leucovorin in 5-fluorouracil-based oxaliplatin- or irinotecan-containing regimen in metastatic colorectal cancer
Authors: Song E. , Lee N. , Kwak J. , Yhim H. , Lee K. , Roh H. , Sohn M. , Yim C. 
Published: August 2020

e15054 Background: Although leucovorin (LV) is widely used as a modulator of 5-fluorouracil (5-FU) for the chemotherapy of advanced colorectal cancer, the optimal dose has not yet been established. Low-dose LV appears to be as active as high-dose LV in the several studies. So, we tried to compare the efficacy of high-versus low-dose LV in the commonly used palliative chemotherapy regimen. Methods: Between May 2003 and May 2008, 40 patients with metastatic colorectal cancer were randomly treated with high-LV (200mg/m2/i.v.) or low-LV (20mg/m2/i.v.) in 5-FU based oxaliplatin (FOLFOX-4) or irinotecan (FOLFIRI) containing regimen. The primary endpoint of the study was the comparison of response rates and the secondary endpoint was the assessment of survival and tolerability. Results: The response rate was 40% in low-LV group with 2 CR and 6 PR, and 35% in high-LV group with 2 CR and 5 PR, without any significant difference (P = 0.89). The median overall survival was 24.3 months in low-LV group and 25.2 months in high-LV group, with no difference between treatments. Toxicity mainly consisted of gastrointestinal side effects, which were rare and similar in the two groups. Conclusions: In this randomized phase II study, the low and high doses of LV appeared to be equivalent in palliative chemotherapy of metastatic colorectal cancer although large-scale phase III study are necessary. No significant financial relationships to disclose.
Bevacizumab (BV) plus chemotherapy (CT) as first-line treatment of patients with metastatic colorectal cancer (mCRC): First results from a large community-based observational cohort study in Germany
Authors: Arnold D. , Kindler M. , Petersen V. , Tummes D. , Moelle M. , Schoeberl C. , Srock S. , Kutscheidt A. , Grothe W. 
Published: August 2020

e15057 Background: BV prolongs overall survival (OS) and progression-free survival (PFS) when added to standard CT for patients (pts) with mCRC. After approval of BV in Germany in 01/05, this observational cohort study was initiated in pts receiving BV with various first-line CT regimens to evaluate safety events and effectiveness. Methods: To facilitate and evaluate enrollment of a typical mCRC population, eligibility criteria were minimized. Choice of the CT regimen was at physician´s discretion, but influenced by the current registration status. Predefined endpoints were treatment characteristics, response rate (RR), PFS, OS, and adverse events assessed as potentially related to the treatment (AERT) or as severe (SAE). Pts are followed for up to 4 years, and clinical data were updated every cycle (2–4 weeks). Results: 1,300 pts were enrolled at 261 sites from 01/05 through 06/08; abstract data cutoff date was 11/24/08. Median age: 64 (range 19–100) years, > 70 years.: 25%; male 63%; ECOG PS status 0–1/2/>2 88%/11%/1%. CT choice was fluoropyrimidine (FU)/BV alone (any 5-FU or capecitabine) 12%; FU/BV/oxaliplatin 18%; FU/BV/irinotecan 69%; other 1%. Median treatment duration with BV was 7.4 (range 0–28) months; duration > 10 months 21%. 60-day mortality was 4.0%. In total, 183 AERT were reported in 10% of pts., most commonly diarrhea (34 AERT), nausea (26) and hypertension (18). Reported SAE were deep venous TE in 0.8% of pts, bleeding 1.2%, pulmonary embolism 0.5%, arterial TE 0.4%. Best investigator- assessed RR was 59% (CR 10%, PR 49%; all pts) with 64% for FU/BV/oxaliplatin, 59% for FU/BV/irinotecan and 53% for FU/BV alone. Conclusions: The safety profile of BV in this population of mCRC pts with different CT regimens appears consistent with that observed in the other reports like BRiTE or first BEATrial. RR in this preliminary dataset are higher than that reported in the randomized controlled trials, but likely biased by the methodology of evaluation. However, activity with FU/BV alone was surprisingly high. Updated efficacy data including PFS will be presented. [Table: see text]
Targeted plasma proteome profiling for early prediction of chemotherapy response and toxicity in colorectal cancer (CRC)
Authors: Chua W. , Randall S. , McKay M. J. , Horvath L. , Clarke S. J. , Molloy M. P. 
Published: August 2020

e15063 Background: Accurate predictors of chemotherapy response and toxicity in CRC are required to improve the safety, efficacy and costs of treatment. Plasma proteomic profiling using multiple reaction monitoring mass spectrometry (MRM-MS) couples assay multiplexing with high specificity to determine levels of pre-selected biomarker proteins. Our aims were to investigate the utility of plasma proteomic profiling using MRM-MS for predicting: (1) early haematological toxicity, (2) response and (3) survival for patients receiving chemotherapy for CRC. Methods: Patients with locally advanced and metastatic CRC receiving chemotherapy were enrolled. Plasma collection was performed pre-chemotherapy, at day 3 and day 15 of treatment. Toxicity assessments (NCI Criteria v3.0) were prospectively collected for all patients and treatment response (RECIST) assessed for patients with metastatic disease. MRM-MS assays were designed for 39 peptides representing 31 liver derived plasma proteins with reported roles in inflammation and/or cancer. Statistical analysis was performed using the 2-sample t-test to assess statistically significant fold change differences (p<0.05) between sample days for: (1) patients with absence or presence of ≥ Grade 2 neutropenia after two cycles and (2) responders (CR and PR) versus non-responders (SD or PD). Results: Plasma proteomic profiling for 39 peptides was performed for 17 patients. The greatest change in protein levels was observed between Day 3 and 15 with 9% of proteins showing a 1.5 fold or greater change with some proteins showing a ≥ 200-fold change in level. Three proteins (clusterin, paraoxanse and apolipoprotein A1) were significantly different in the group analysed for neutropenia and four proteins (kininogen I, serum paraoxonase/ arylestease 1, apolipoprotein A-1 and complement C4a) were significantly different in the group analysed according to response. Survival analysis was not performed due to the short follow up. Discussion: Our results are encouraging for the use of a robust mass spectrometry technique for early prediction of neutropenia and chemotherapeutic response in CRC. No significant financial relationships to disclose.
Evaluation of thymidylate synthase and ERCC1 mRNA levels as predictive markers in colorectal cancer patients treated with S-1 and oxaliplatin
Authors: Kuramochi H. , Hayashi K. , Nakajima G. , Kamikozuru H. , Yamamoto M. 
Published: August 2020

e15071 Background: Oxaliplatin has been widely used for the treatment of colorectal cancer. The mechanism of action of platinum compounds such as oxaliplatin is to bind to a DNA molecule in the form of a platinum-DNA-adduct. Excision repair cross complementation group 1 (ERCC1), which plays a major role in the nucleotide excision pathway, has a polymorphism in codon 118, and is reported to be associated with a resistance to platinum-based therapy. Thymidylate synthase (TS) and dehydropyrimidine dehydrogenase (DPD) are key enzymes of 5-FU metabolism and are well known to be associated with a response to 5-FU-based therapy. Methods: Twenty-one colorectal cancer patients (male:female = 7:14; median age, 65) treated with a combination of oxaliplatin and S-1 as a first-line therapy were analyzed for ERCC1 codon 118 polymorphism and the mRNA expression levels of TS, ERCC1, and DPD. Formalin-fixed paraffin- embedded surgical specimens were used and t-RNA and DNA were extracted. The mRNA expression levels were measured using real-time RT-PCR, and the polymorphism was analyzed using the allelic discrimination method together with real-time PCR. Results: No correlation was observed between ERCC1 codon118 polymorphism and any response to the chemotherapy. ERCC1 mRNA levels tended to be higher in the patients with wild-type homozygous alleles in codon 118 than in those with at least one mutant allele(1.19 vs.0.68: p= 0.15). Patients with both high TS and ERCC1 mRNA levels showed a significantly lower response rate than the others (25% vs. 67%, p=0.02). No relationship was seen between DPD mRNA expression levels and the response. Conclusions: The mRNA expression levels of TS and ERCC1 appear to be useful markers for the treatment of S-1 and oxaliplatin. No particular usefulness of ERCC1 codon 118 polymorphism was verified. No significant financial relationships to disclose.
A phase I trial of a bi-weekly combination of capecitabine/irinotecan (XELIRI) then capecitabine/irinotecan/oxaliplatin (XELIRINOX) in solid tumors
Authors: Assenat E. , Kramar A. , Poujol S. , Gestin-Boyer C. , Senesse P. , Samalin E. , Portales F. , Thezenas S. , Bleuse J. , Ychou M. 
Published: August 2020

e15075 Background: Oral fluoropyrimidines, notably capecitabine, are increasingly replacing IV 5-FU/LV as the backbone of therapy for metastatic colorectal cancer. The bi-weekly combination of capecitabine/irinotecan warrants further examination. Methods: We conducted a phase I trial, in metastatic cancer patients treated for solid tumors, to determine the recommended dose of capecitabine administered orally bid from day 1 to 8 in combination with a bi-weekly fixed-dose of IV irinotecan 180 mg/m2 delivered on day 1 and 14 (FIRST STAGE: XELIRI); and + a bi-weekly fixed-dose of IV oxaliplatin (L-OHP) 85 mg/m2 delivered on day 1 and 14 (Second STAGE: XELIRINOX). Five increasing dose levels (DL1–5) of capecitabine were planned: 1000, 1250, 1500, 1750, and 2000 mg/m2 bid. A pharmacokinetic study of this association was performed. Results: In the first stage, a total of 17 patients were enrolled, with a median age of 60 (range 52–73) years. All patients had an ECOG PS of either 0 (59%), 1 (35%), or 2 (6%). Four patients experienced dose-limiting toxicity: 2 developed grade 4 neutropenia (at DL 1 and 4) and 2 others grade 4 febrile neutropenia (at DL3 and 4). One toxicity-related death occurred following febrile neutropenia (DL4). Maximal tolerated dose (MTD) was DL4, and the recommended dose regimen was bi-weekly irinotecan 180 mg/m2 combined with capecitabine 1500 mg/m2 bid (administered from days 1 to 8). In the second stage, the starting dose level of capecitabine in the bi- weekly association with irinotecan and L-OHP was defined as two dose levels below the MTD level reached in the first stage of the study (DL4 - 2 = DL2). Height patients were enrolled with a median age of 56 (35–75) and ECOG 0 for 62%, ECOG 1 for 38%. Chemotherapy is ongoing for three of them. Three patients experienced dose-limiting toxicity: 1 grade 4 neutropenia ( DL2), 1 grade 4 febrile neutropenia ( DL3) and 1 grade 4 pneumopathy ( DL3). The MTD of XELIRINOX was DL3, and the recommended dose regimen will be presented at the meeting. Conclusions: Bi-weekly combination of capecitabine/irinotecan/oxaliplatin (XELIRI / XELIRINOX) is feasible and could be tested in patients with metastatic colorectal cancer in combination with a targeted therapy. [Table: see text]