bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose-escalation study using up to twice the standard dose of cetuximab in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST study): Preliminary data
Authors: Tejpar S. , Peeters M. , Humblet Y. , Gelderblom H. , Vermorken J. , Viret F. , Glimelius B. , Ciardiello F. , Kisker O. , Van Cutsem E. 
Published: March 2020

3554 Background: Response to the epidermal growth factor receptor (EGFR) inhibitor, cetuximab appears to correlate with the intensity of the associated skin reaction. This randomized multicenter study investigated the effect of cetuximab dose escalation on EGFR activation and downstream signaling in skin and tumor biopsies, on activity and skin reactions in patients (pts) with EGFR-expressing mCRC, failing prior irinotecan (I). Methods: Pts with ≥1 measurable lesion suitable for biopsy were eligible and were randomized 22 days after starting treatment with cetuximab (initial dose 400mg/m2 then 250mg/m2/week(w)) plus I (2-weekly regimen 180 mg/m2) if they had not experienced >grade 1 skin reaction, any other >grade 2 cetuximab-related toxicity and were not intolerant to I. Pts were randomized to standard cetuximab dose (arm A; 250 mg/m2/w) or dose-escalation (arm B; cetuximab dose increased by 50 mg/m2 q 2 w up to 500 mg/m2, until >grade 2 toxicity or tumor response). Pts not randomized (arm C) continued with the standard regimen after day 22. Skin and tumor biopsies were taken pre- and during treatment. Results: Of 273 screenedpts, 221 were EGFR-expressing and 166 were recruited. 45 pts were randomized to arm A, 44 to arm B and 76 were in arm C. By August 2005, 18 pts had reached the highest dose (500mg/m2/w), with no concerns over safety. All baseline and second biopsies are available. Safety results are presented for the first 36 pts in arm B. M/F 23/13, median age 60 y (34–79), median Karnofsky performance score 90 (80–100). All pts reported here had received cetuximab for at least 6 weeks. Maximum dose reached at w 6: 350mg/m2/w (300mg/m2 in 36 pts at w 4; 350mg/m2 in 31 pts at w 6). Relevant grade 3/4 toxicities were diarrhea (2.8%) and fatigue (5.6%). No grade 3/4 skin reactions occurred. Conclusions: Cetuximab at a dose of 350 mg/m2 is well tolerated in pts who have had no or mild skin reactions in response to standard dose treatment. Further dose escalation is possible. No early increase of skin toxicity is observed. Analysis of efficacy and pharmacokinetics/dynamics is ongoing. [Table: see text]
Phase I/II study of cetuximab, capecitabine and oxaliplatin (CAPOX) combined with standard radiotherapy (RTX) as neoadjuvant treatment of advanced rectal cancer (RC)
Authors: Arnold D. , Hipp M. , Reese T. , Hohenberger W. , Liersch T. , Lordick F. , Sülberg H. , Sauer R. , Rödel C. 
Published: March 2020

3574 Background: CAPOX given concurrently to neoadjuvant RTX in RC is well tolerated and yielded high rates of pathologic complete responses in phase II trials. Cetuximab, a monoclonal antibody targeted against the EGF receptor, is active in metastatic colorectal cancer. Furthermore, synergy of cetuximab with RTX was shown in improved survival vs. RTX alone in head and neck cancer. This trial was to evaluate maximal tolerated dose (MTD), feasibility and efficacy of CAPOX + RTX with cetuximab in RC. Method: Patients (pts) had to have unpretreated T3–4 and/or N+ disease, with distant metastases allowed. During a conventionally fractionated RTX (1.8 Gy for 28 days [d]), cetuximab was given in standard dosage (400mg/m2 on d-7, then 6 weekly doses of 250 mg/m2, to d35). CAPOX was given on the basis of a previously examined schedule with oxaliplatin (50 mg/m2 d 1,8,22 and 29) in combination with capecitabine (d1–14 and d22–35) at 3 dose levels: 1000, 1300 and 1650mg/m2 bid. In phase I, a standard 3+3 design was used, allowing for dose escalation in 0/3 or 1/6 pt with dose-limiting toxicity (DLT). Results: 13 pts were enrolled: Median age 58 [35–75] yrs., m/f 7/6 pts. T3 85%, T4 15%; N+ 92%, M1 46%; G2 92%, G3 8%. As on dose level 1 one DLT (diarrhea grade 3) occurred, it was extended to 7 pts. No further DLT was observed as it was on levels 2 and 3 with 3 pts each. Full RTX course was administered in all pts, while CAPOX-cetuximab was stopped in the DLT case and cetuximab in 1 pt with hypersensitivity reaction. Toxicities are displayed in the table . Conclusion: CAPOX can safely be combined with cetuximab without requiring chemotherapy dose reduction. The multicenter phase II part of the trial with 31 pts. included so far is ongoing and updated results (including resectability) will be presented. [Table: see text] [Table: see text]
A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (CPT-11 + oxaliplatin [IRINOX]) and two standard arms (LV5-FU2 + CPT-11 [FOLFIRI], LV5-FU2 + oxaliplatin [FOLFOX]) in first line metastatic colorectal cancer (MCRC) (FNCLCC Accord 08)
Authors: Becouarn Y. , Ychou M. , Boucher E. , Adenis A. , Cany L. , Jacob J. , Cvitkovic F. , Thezenas S. , Montoto-Grillot C. 
Published: March 2020

3586 Background: LV5-FU2 + CPT-11 or oxaliplatin (OHP) are standard therapies in first line MCRC. This phase II trial evaluates an experimental regimen of CPT-11 + oxaliplatin, without 5FU. Methods: First line MCRC evaluable patients (pts) were randomized to receive, every two weeks, either: Arm A = OHP 85 mg/m2 d1 followed by CPT-11 180 mg/m2 (IRINOX), or Arm B = simplified LV5-FU2 (leucovorin 200 mg/m2 as a 2 h-infusion d1, 5FU bolus 400 mg/m2 d1, and 5FU continuous infusion 2400 mg/m2 d1–2) and CPT-11 180 mg/m2 d1 (FOLFIRI), or simplified LV5-FU2 and OHP 85 mg/m2 d1 (FOLFOX). Results were combined for the two standard arms (FOLFIRI + FOLFOX). Results: 80 pts were included between 09/2002 and 04/2005, 40 in IRINOX (arm A), 20 each in FOLFIRI and FOLFOX (arm B). Pts characteristics (A:B): M/F = 27/13:29/11; median age (range): 63 (41–76):61 (47–75); PS (0/1/2): 16/21/3:16/22/2; median number of cycles (range): 8.0 (1–16):12 (1–26). Safety data: no toxic death. IRINOX (318 cycles): NCI G3–4 neutropenia, 43.6% (pts), 14.7% (cycles); G3–4 neurotoxicity, 17.9% (pts), 5.0% (cycles); G3–4 diarrhea, 33.3% (pts), 5.3% (cycles). FOLFIRI (238 cycles) and FOLFOX (186 cycles): G3–4 neutropenia, 40% (pts) and 23.8% (pts) respectively (8.8% and 7.6% of cycles); G3–4 neurotoxicity, 0% and 14.3% (pts), 0% and 2.7% (cycles); G3–4 diarrhea 15% and 0% (pts), 2.1% and 0% (cycles). Median relative dose-intensity was 0.86 (0.57–1.0) for CPT-11, 0.86 (0.57 -1.0) for OHP in the IRINOX arm. We observed 21 PR in the IRINOX arm, 19 PR and 2 CR in the 2 control arms, for an ORR = 52.5%, 90% CI (38–66). Median follow-up: 17 months, median PFS for IRINOX: 8.4 months. Conclusions: The combination of CPT-11 and OHP (IRINOX) at these doses, every 2 weeks, appears safe and active in first line MCRC. [Table: see text]
Biweekly oxaliplatin plus capecitabine (OXXEL) versus oxaliplatin plus folinic acid-modulated 5-fluorouracil i.v. bolus (OXAFAFU) in metastatic colorectal carcinoma (MCC): Safety interim analysis of a Southern Italy Cooperative Oncology Group (SICOG) phase III trial
Authors: Sandomenico C. , Filippelli G. , Massidda B. , Farris A. , Natale D. , Palmeri S. , Maiorino L. , Condemi G. , Leo S. , Greco E. , Gambardella A. 
Published: March 2020

3590 Background: We have previously reported that OXAFAFU regimen significantly prolonged the overall survival of MCC patients (pts) in comparison with IRIFAFU regimen (Comella, Ann Oncol 2005). Moreover, the OXXEL regimen showed promising activity in phase II study (Comella, Cancer Chemother Pharmacol 2005). Comparison of these two regimens in terms of safety and activity is the aim of the present trial. Methods: Pts with MCC were randomly treated with: oxaliplatin 85 mg/m2 iv on day (D) 1, levo-folinic acid 250 mg/m2 plus 5-fluorouracil 850 mg/m2 bolus iv on D 2 (OXAFAFU); or oxaliplatin 100 mg/m2 iv on D 1, Xeloda 1,000 mg/m2 twice daily po from D 1 (evening) to D 11 (morning). Treatment was delivered every 2 weeks up to progression, or for a maximum of 12 cycles. Results: From May 2004 to December 2005, 191 eligible pts were recruited (OXAFAFU, 96 pts; OXXEL, 95 pts). Characteristics of pts were well balanced in OXAFAFU vs OXXEL arm: primary colon, 74% vs 72%; PS 0/1–2, 57/43% vs 65/35%; previous adjuvant CT, 24% vs 20%; liver metastases, 80% vs 83%; ≥ 2 metastatic sites, 54% vs 49%. At this interim analysis, with a median number of 8 (range, 1–12) cycles delivered in both arms, 143 pts (OXAFAFU, 73; OXXEL, 70) were assessed for safety. In OXAFAFU vs OXXEL arm, occurrence of WHO grade ≥ 3 toxicity was: neutropenia, 29% vs 3%; anemia, 2% vs 7%; thrombocytopenia 3% vs 7%; diarrhea, 4% vs 13%; vomiting, 4% vs 3%; hand-foot syndrome, 1% vs 7%. Conclusions: At this interim analysis, the OXXEL regimen appeared to produce significantly less neutropenia than the OXAFAFU regimen, at a price of an acceptable non-hematologic toxicity. Accrual will continue up to reaching the final sample size of 300 pts. No significant financial relationships to disclose.
Phase II study of oral S-1 monotherapy in metastatic colorectal cancer after failure of both irinotecan and oxaliplatin-containing regimen
Authors: Cho B. , Choi H. , Jeung H. , Rha S. , Ahn J. , Roh J. , Kim Y. , Chung H. 
Published: March 2020

3597 Background: There has been a considerable increase in the number of patients (pts) with mCRC pretreated with both irinotecan and oxaliplatin. Little is known about third-line therapy in this group of pts. We conducted a phase II trial of oral S-1 in pts with advanced colorectal cancer who failed on both irinotecan and oxaliplatin. Methods: This phase II study was designed to evaluate the activity and toxicity of S-1 monotherapy in 31 advanced colorectal cancer pts (P0 = 3%, P1 = 15%; α = 0.05, power = 80%, drop-out rate 10 %). S-1 was administered orally twice daily, 70 mg/m2/day for 14 days followed by 1-week rest. Eligibility criteria included ECOG 0–2; measurable lesion; adequate organ functions; signed informed consent. Results: As of 1st September 2005, 21 pts were enrolled. Median age of all pts 55 years. There were 10 male and 11 females. Thirteen of 21 patients were treated with oxaliplatin-containing regimens as a first-line therapy for metastatic diseases. The median number of treatments was 3 courses (range, 1–10). The relative dose intensity was 1.0 (0.83 - 1.0) with a median dose of120 mg (100 -140 mg). Nineteen out of 21 patients were evaluable. The confirmed response rate was 21.1% (4/19, 1 CR, 3 PR). The median PFS was 11 weeks, and median OS was not reached. The most frequent adverse reaction was skin pigmentation (47.6%). Grade 3 toxicities was skin pigmentation in 1 patients (4.8%), neutropenia in 1 (4.8%), and anemia in 1 (4.8%), respectively. Conclusion: This results shows that S-1 produces a promising response rate with an acceptable safety profile in refractory, mCRC. S-1 has the potential to become a valuable option as a third-line salvage regimen in irinotecan and oxaliplatin pretreated mCRC pts. Clinical trial of combination therapy with S-1 will be warranted. No significant financial relationships to disclose.
5,10-methylenetetrahydrofolic acid with 5-fluorouracil as first line treatment in metastatic colorectal cancer: Phase II study results
Authors: Reid T. , Spears C. P. , Quadro R. , Subramanian M. , Pawl L. , Jankovic G. , Jelic S. , Milinic N. , Muzikravic L. , Robbins J. 
Published: March 2020

3599 Background: 5-Fluorouracil (FU) plus Leucovorin (LV) has historically been the standard first line treatment of colorectal cancer. Although LV modestly enhances FU activity, it can increase systemic toxicity and also must be intracellularly converted in multiple steps to its active metabolite, 5,10-methylenetetrahydrofolate (CoFactor [CO]). Unlike LV, CO directly modulates FU inhibition of thymidylate synthase without the need for metabolic conversion. Preclinical models show reduced hematologic toxicity of CO+FU with enhanced efficacy compared to FU+LV. We evaluated CO+FU chemotherapy in patients with previously untreated mCRC. Methods: Patients (pts) had performance status ECOG 0–2 and objectively measurable mCRC. Prior adjuvant therapy was allowed including FU+LV. Fifty pts were enrolled and treated with CO 60mg/m2 and FU 450mg/m2 (weekly IV bolus) for 6 weeks, followed by 14 day rest. Response was measured at 16 wks (WHO criteria). Results: As of January 2006, 50 pts received at least 1 dose of drug and are no longer on treatment. Patient demographics: median age = 65 (range 42–86), M/F = 60%/40%. Mean number of doses was 18.0 (range 2–41). Overall incidence of grade 3/4 AEs was 14 (28%). No grade 3/4 drug-related hematologic toxicity was observed. There was no significant effect on HCT, Bili, WBC, ALT, and AST during the course of the study. Objective response rate (CR + PR) to first line treatment with CO+FU based on independent blinded review was 35% (2 CR, 14 PR, 23 SD, 7 PD; 95% CI: 21.4–50.2) based on 46 pts evaluable for response. Median time to tumor progression was 163 days (95% CI: 105 -189). Twenty pts are deceased and median survival has not been reached. Conclusions: The results suggest thatCO+FU is safe, well tolerated, and has activity in mCRC. In the optimum treatment strategy afforded by the availability of numerous drugs, the high level of activity and low toxicity of CO+FU suggests that this combination may be a good initial treatment in a sequential strategy of mCRC management, especially among pts who would benefit by minimizing initial toxicity. [Table: see text]
Gene expression of MLH1 related to microsatellite instability, immuno-histochemistry, and promoter hypermethylation in colorectal cancer
Authors: Jensen L. H. , Jakobsen A. , Kuramochi H. , Liu B. , Stephen C. L. , Crüger D. G. , Aggerholm A. , Lindebjerg J. , Danenberg P. V. , Danenberg K. D. 
Published: March 2020

3601 Background: The subgroup of highly microsatellite instable (MSI-H) colorectal cancers (CRC), is well described with DNA microsatellite and immuno-histochemistry (IHC) analyses. MSI-H CRCs are most often caused by hypermethylation inactivation of MLH1 or to a lesser extent by hereditary mutations in this or other mismatch repair genes. Microsatellite analysis and IHC are qualitative rather than quantitative methods. Reports showing that MMR deficient CRC has a favorable prognosis and that these cancers may respond less to chemotherapy may be more informative if based on a quantitative method instead. The aim of the present study was to correlate the expression of MLH1 to microsatellite analysis, promoter hypermethylation, and IHC. Methods: Sections of paraffin-embedded tumors from 206 unselected consecutive patients with CRC were microdissected and RNA was isolated and reverse-transcribed to cDNA. The relative gene expression of MLH1 was measured with real-time PCR. DNA from tumor and blood was examined with five standard microsatellite markers to find length mutations indicating instability. Tumor DNA was further analyzed with a methylation specific PCR in the C region of the MLH1 promoter. Protein expression of MLH1 was analyzed with IHC. Results: For all quantifiable tumors the median (and lower and upper quartiles) of the relative MLH1 gene expression was 0.90 (0.68, 1.42). For MSI-H tumors, defined as presense of instability in at least two markers or lack of protein expression with IHC, the median was 0.36 (0.26, 0.56). For microsatellite stable cancers the median was 0.96 (0.73, 1.44), p<0.0001 (Wilcoxon test). Median and quartiles of MLH1 expression in hypermethylated and non-methylated tumors was 0.31 (0.26, 0.45) and 0.96 (0.73, 1.43) respectively (p<0.0001). Relative MLH1 expression in MSI-H tumors range up to 0.64. Fourteen % of MSS tumors are in this range, too. Conclusions: In this large unselcted group of CRC patients we found a significant relation between low gene expression, MSI-H, MLH1-hypermethylation and negative IHC. We further identify a subgroup of MSS patients with low gene expression of MLH1 and suggest this quantitative marker in studies of prognosis and treatment effect. [Table: see text]
Novel blood biomarker panel detects human colorectal cancer
Authors: Han M. , Liew C. T. , Zhang H. W. , Yip K. T. , Song Z. Y. , Li H. M. , Geng X. P. , Zhu L. X. , Marshall K. W. , Liew C. C. 
Published: March 2020

3611 Background: Human colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States, and early detection is critical to improve prognosis. To date, we have applied our unique methodology (the Sentinel Principle) to identify blood-based gene expressed biomarkers for several diseases including osteoarthritis, bladder cancer and psychiatric disorders. In the present CRC study, we identified gene signatures from blood cells and characterized a set of biomarkers able to differentiate patients with CRC from controls. Methods: Microarray: 31 blood RNA sample (15 controls; 16 CRC) were profiled using Affymetrix U133Plus2.0 GeneChips. Differentially expressed genes were identified using the non-parametric, Wilcoxon-Mann-Whitney test. SYBR Green real-time RT-PCR: a subset of identified genes was assayed using 115 samples (57 controls; 58 CRC). Logistic regression was used to assess the ability of linear combinations of specific transcripts to distinguish CRC from controls. The diagnostic power for each combination was evaluated by AUC of the Receiver Operating Characteristic (ROC) curve. Blind Test: 83 samples were assayed (45 controls and 38 CRC). Results: Microarray data: 2,779 probes were significantly different in blood gene expression profiles from controls and those from CRC (p<0.05). Real-time RT-PCR: Two up-regulated genes (cytidine deaminase, 1.3 fold with p<0.001; MGC20553 /FERM domain containing 3, 1.2 fold with p=0.031) and three down-regulated genes were validated (B-cell scaffold protein with ankyrin repeats 1, 0.43 fold with p<0.001; B-cell novel protein 1, 0.44 fold with p<0.001; membrane-spanning 4-domains, subfamily A, member 1, 0.44 with p<0.001). Combination analysis: The AUC was 0.883 (95%, C.I. 0.810–0.935) for the best linear combination of these 5 genes. At a cut-off of -1.1, the sensitivity and specificity were 98% and 51%, respectively. Blind Test: The 5-gene set gave sensitivity of 95% (36/38) and specificity of 42% (19/45) with an overall accuracy of 66%. Conclusions: Gene expression signatures from peripheral blood differentiate between CRC patients and controls. The five-gene panel showed high classification performance and could be used as a novel screening tool for CRC. [Table: see text]
Benefits, limitations and pitfalls of sentinel lymph node (SLN) mapping (M) for colorectal carcinoma (CRCa): A multicenter trial
Authors: Saha S. , Sehgal R. , Patel M. , Wiese D. , Bilchik A. , Beutler T. , Iddings D. , Espinosa M. , Yee C. , Ghanem M. 
Published: March 2020

3621 Background: Clinical application of SLNM in CRCa patients (pts) is controversial due to the variable results in the literature for its success, skip metastases (mets) and accuracy. Hence prospective data from 5 institutions were analyzed to identify the factors associated with failure and skip mets in CRCa pts undergoing SLNM. Methods: SLNM was performed by peri-tumoral injections of 1–3 ml of 1% lymphazurin subserosally. First 1–4 blue nodes marked as SLNs were examined by 4 sections with H & E and 1 for cytokeratin. Rate of failure and skip mets rate along with age, sex, tumor site, size, grade, T & N stages were analyzed. Results: 549 consecutive CRCa pts underwent SLNM; 453 colon (C) and 96 rectal (R) pts. M: F ratio was 48%: 52% and median age of 72 years. The average no. of LNs was 14.5. SLNM failed in 1% of C and 8% of R pts ( Table ). Of the 8 R failures, 7 had neoadjuvant therapy. No correlation was found between failure, size or T-stage. Overall nodal positivity (+ve) rate was 48%. Of the 466 invasive CRCa pts with successful SLNM, rate of skip mets was 7% in C and 4% in R. Age, sex, grade and neoadjuvant therapy had no correlation with skip mets. Of 28 skip mets pts, 79% had tumors >3cm and 93% had advanced (T3, T4) tumors. Higher skip mets also was found in the transverse colon tumor. The success, accuracy, and sensitivity rates were 98%, 95%, and 88% respectively. Of node +ve pts, 47% had mets found only in the SLNs. SLNM upstaged 35% of C and 36% of R pts with micromets. Conclusions: In CRCa, SLNM is highly successful and accurate in predicting the presence or absence of nodal mets. Submucosal fibrosis of the lymphatics due to neoadjuvant therapy may result in higher failure rates for R pts. Skip mets are higher in transverse C tumors and increase in frequency as the T-stage increases. Pts upstaged by SLNM may benefit from adjuvant chemotherapy. [Table: see text] No significant financial relationships to disclose.
lymphadenectomy for liver tumors: A safe procedure in a tertiary center which improves the staging of the disease
Authors: Ravaioli M. , Ercolani G. , Grazi G. , Cescon M. , Varotti G. , Del Gaudio M. , Vetrone G. , Zanello M. , Tuci F. , Pinna A. 
Published: March 2020

3622 Background: the role of regional lymphadenectomy for liver metastases and primary liver tumors, but not extra-hepatic bile duct cancer, is debated. Methods: from April ’99 to December ’04, we prospectively evaluated 142 patients treated with liver resections and with the following pre-operative diagnosis: 63 (44.4%) colorectal metastases (M-CR), 48 (33.8%) hepatocellular carcinoma (HCC), 16 (11.3%) non-colorectal metastases (M-NCR) and 15 (10.6%) intra-hepatic cholangiocellular carcinoma (CCC). The regional lymphadenectomy of the hepato-duodenal ligament and of the common hepatic artery was performed in all cases. The incidence and the influence on survival of lymph node metastases were analyzed. Results: 42 “wedge” resection (29.6%), 55 segmentectomies (38.7%) and 45 major hepatectomies (31.7%) were performed. The mean operative time was 292±131 minutes and 96 cases (67.6%) had no blood transfusions during the procedures. Operative mortality (within 30 days) was 3.5%, 48 cases (33.8%) developed post-operative complications and the most common was ascites. The mean hospital stay was 9±5 days. The mean number of nodes (LN) removed were 6.5±5 (range 6–30) and 63 LN (6.5%) had micro-metastases. The incidence of lymph node metastases (LN+) according to the pre-operative diagnosis was: 15.9% M-CR, 4.2% HCC, 37.5% M-NCR and 40% CCC. The mean follow-up was 37.4±22.6 months, 107 patients (75.4%) are alive and 44 (31.7%) developed tumor recurrence, which was more frequent in LN+ (54.2% vs. 27%, p<0.05). The 1-and 3-years patient survival was significantly affected by lymph node metastases: 92% and 85% LN- vs. 79% and 64% LN+, p<0.05. Conclusions: the regional lymphadenectomy for liver tumors is a safe procedure in tertiary referred centers. The presence of lymph node metastases was an important prognostic factor, which should be evaluated to improve the treatment strategies. No significant financial relationships to disclose.