bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-line single-agent cetuximab in patients with advanced colorectal cancer
Authors: Pessino A. , Artale S. , Guglielmi A. , Sciallero S. , Fornarini G. , Andreotti I. C. , Mammoliti S. , Marrapese G. , Siena S. , Sobrero A. 
Published: March 2020

3553 Background: The most relevant recent advance in the treatment of metastatic colorectal cancer is the fact that cure is still possible under very selected conditions. However the goal of chemotherapy remains palliative in the great majority of patients, justifying less toxic innovative approaches in so- called “window of opportunity trials”. We have pursued this idea in a phase II study of cetuximab monotherapy in chemo-naive patients with advanced colorectal cancer beyond any possibility of curative resection. Methods: Patients with non-resectable metastatic colorectal cancer (at least two metastatic sites and/or otherwise inoperable metastatic disease) were treated with cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) until progressive disease (PD) or unacceptable toxicity. The primary end-point was objective response; secondary end-points were: stable disease, time to treatment failure and time to progression. According to Simon’s two-stage design, the number of responses/patients to stop the trial was 0/10 for stage 1 and 3/29 for stage 2. Results: Of the 44 patients screened, 42 (97%) had EGFR-expressing tumors. Thirty-nine patients (median age: 69) initiated the treatment. Two had grade 3 allergic reactions to cetuximab at the first administration leading to treatment discontinuation. The most common adverse event was skin toxicity, which occurred in 90% of the patients ( 31% grade 2, 10 % grade 3). We observed 1 complete response, 3 partial responses, 13 stable diseases (5 of which were minor responses), and 22 PD. The duration of the 4 responses were 12, 9, 9 and 6 months. Median time to progression was 2.0 months. Conclusions: The study is negative because the response rate is low. However, the duration of benefit in the few responding patients is such that it is imperative to find the molecular determinants of cetuximab activity in these cases. [Table: see text]
Cetuximab in combination with irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFIRI) in second and third-line treatment of metastatic colorectal cancer (mCRC): Safety and efficacy analysis
Authors: Smith D. M. , Legoux J. , Brunet R. , Adhoute X. , Blanc J. , Fonck M. , Vendrely V. , Becouarn Y. 
Published: March 2020

3558 Background: The Folfiri regimen demonstrated high efficacy and favorable safety profile compared to irinotecan plus bolus 5-FU/FA (IFL regimen) or irinotecan alone. Folfiri is a standard option in first line treatment of mCRC. Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), which is commonly expressed in mCRC, is approved in France in combination with irinotecan after failure of an irinotecan-based therapy. We have prospectively evaluated the combination cetuximab-FOLFIRI in patients with mCRC refractory to FOLFIRI administered in first line treatment. Methods: Patients with EGFR-expressing mCRC, who progressed following first line treatment with FOLFIRI regimen were eligible for this study. Treatment consisted of cetuximab (initial dose 400 mg/m2 followed by 250mg/m2/week) combined with FOLFIRI (given every 2 weeks: irinotecan 180 mg/m2, FA 400 mg/m2 and 5-FU 400 mg/m2 bolus plus 2400 mg/m2/46-h infusion) until either disease progression or unacceptable toxicity. Tumor reponse was assessed by CT scan every 2 months (OMS criteria), and adverses events were registered. Results: 41 patients where included from 09/2004 to 11/2005. 78% Male/ 22% Female, mean age 63 years, median KPS 80, 68% colon primary tumour. 5 patients were treated in second line, 24 patients in third line and 12 in fourth line or more. 40 patients are evaluable for response. They were 8 objective responses (20%) and 11 patients with stable disease (27.5%). The median progression free survival was 4,3 months and the median overall survival was 5 months. 61 % of the 41 patients experienced grade 3–4 adverses events, the most frequent of which were leucopenia (16%), asthenia (9%), vomiting and diarrhoea (5%), and acneiform skin rash in 11 patients (24%), severe xerosis (7%). 6/11 patients who experienced acneiform eruption grade 3 were alive at 12 months. Conclusions: The combination of cetuximab with FOLFIRI demonstrated promising efficacy and acceptable safety profile without increasing chemotherapy adverse reactions. A prospective randomised trial would confirm the advantage of FOLFIRI over irinotecan alone in combination with cetuximab. No significant financial relationships to disclose.
Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer
Authors: Chung K. Y. , Minsky B. , Schrag D. , O’Reilly E. , D’Adamo D. , Hollywood E. , Quinones M. , Saltz L. 
Published: March 2020

3560 Background: Cetuximab, a chimeric anti-EGFR monoclonal antibody, has clinical activity in colorectal cancer with demonstrated safety, efficacy and additive synergy with radiation in solid tumors (head & neck, lung). A pilot trial was therefore designed to investigate the safety of cetuximab in combination with standard neoadjuvant protracted infusion 5-FU and radiation therapy in ultrasound T3–4 (uT3–4) or clinical T4 (cT4) or locally recurrent rectal adenocarcinoma. Secondary objectives of clinical activity were assessed by R0 resection and pathologic complete response (CR) rates. Methods: uT3–4 or cT4 or locally recurrent rectal adenocarcinoma patients received cetuximab 400mg/m2 day 1 (250mg/m2 weekly thereafter) and 5-FU IVCI (225mg/m2) over 5.5 weeks with concurrent pelvic radiation (5040cGy), and cetuximab (250mg/m2 Qweek) for 4 additional weeks, followed by surgical resection 1–3 weeks later. Results: Total Treated: 20 patients (ages 27 - 72), 19 uT3 patients, 1 Local Recurrence patient. Cetuximab Therapy (10 planned treatments): Too early 2 pts, ≥ 8 doses 12 pts, 5 - 8 doses 2 pts, < 5 total doses 4pts* (*cetuximab not given due to: 1 pt - acute cholecystitis from cholelithiasis; 1 pt - Grade 3 radiation perineal toxicity; 2 pts - treatment non-compliance). Radiation Therapy - 18 pts completed, 2 pts too early. Grade 3/4 Toxicities: Diarrhea 10%, Acneiform Rash (outside RT field) 15%, Stomatitis 5%, Radiation Field Dermatitis 5%, Transaminitis 5%. Surgical Outcomes: (17 pts completed surgery): R0 Resection 100%, Pathologic CR 12%. Conclusions: Cetuximab in combination with protracted infusion 5-FU and concurrent radiation is feasible without synergistic or unexpected toxicities. Further randomized investigation of this regimen in the neoadjuvant setting for rectal cancer is warranted. No significant financial relationships to disclose.
Irinotecan in first line therapy of elderly and non-elderly patients with metastatic colorectal cancer: Meta-analysis of four trials investigating 5-FU and irinotecan
Authors: Folprecht G. , Rougier P. , Saltz L. , Van Cutsem E. , Douillard J. Y. , Sastre J. , Mitry E. , Hecker H. , Schubert U. , Köhne C. H. 
Published: March 2020

3578 Background: Irinotecan has been shown to improve response rate and progression free survival in three randomized studies. In a recent metaanalysis showed that elderly patients have a similar benefit from 5-FU containing palliative treatment as younger patients (Folprecht 2004). Methods: We performed a metaanalysis of three randomized trials investigating 5-FU/FA/irinotecan vs. 5-FU/FA (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986]), and one phase II trial with 5-FU/irinotecan (Sastre 2005) to explore the efficacy and toxicity in elderly (≥70 years) and non-elderly (< 70 years) patients. Only data from randomized trials were used to compare the treatment arms 5-FU/FA plus irinotecan (IFL, FOLFIRI or Irinotecan/AIO) vs. 5-FU/FA (Mayo clinic regimen, LV5FU2 or AIO). Results: In total, 303 patients ≥70 y. and 1181 patients < 70 y were analyzed. Overall response rate was 39.5% in elderly and 33.1% in non-elderly patients (p=.055). Progression free survival was 6.7 (5.6–7.8) and 5.7 (5.2–6.1) months in elderly and younger patients (p=.12), respectively, overall survival 15.9 (13.6–18.3) vs. 15.4 (14.3–16.5) months (p=.9). Neutropenia gr. 3/4 and stomatitis gr. 3/4 was found to be more frequent in elderly patients. No differences were found in the other toxicities. Conclusion: The analysis confirms that neutropenia and stomatitis is moderately increased in elderly patients. However elderly patients benefit from treatment with irinotecan/5-FU in a similar way as younger patients do, and (fit) elderly should be offered the irinotecan-containing therapy in the same way as younger patients. [Table: see text] No significant financial relationships to disclose.
A randomised phase II study comparing irinotecan (IRI) plus leucovorin (LV) and 5-fluorouracil (5FU) versus IRI-LV-5FU followed be oxaliplatin (OXA) plus LV-5FU in patients with previously untreated metastatic colorectal cancer (CRC)
Authors: Kalofonos H. P. , Papakostas P. , Aravantinos G. , Papadimitriou C. , Pentheroudakis G. , Varthalitis I. , Tsavdaridis D. , Syrigos K. , Kosmidis P. , Fountzilas G. 
Published: March 2020

3583 Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework supports the hypothesis that sequential administration of cytotoxic drugs at adequate doses can maximize the cell kill and overcome drug resistance. The aim of the study was to compare the response rate (RR), the time to tumor progression (TTP), the overall survival (OS) and to assess the toxicity profile of previously untreated patients with advanced CRC randomly assigned between IRI-LV-5FU (arm A) versus IRI-LV-5FU followed by OXA-LV-5FU (arm B). Methods: Intent to treat analysis was performed on 429 patients (219 in arm A and 210 in arm B) who were randomized from 31/10/2001 to 21/10/2004. The treatment schedules consisted of weekly IRI, 80 mg/m2 or OXA, 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5FU, 450 mg/m2 for 6 weeks followed by a 2-week rest period. Treatment was continued for 4 cycles, patients in arm B were treated initially with IRI-LV-5FU for 2 cycles followed by sequential administration of 2 cycles of OXA-LV-5FU. Results: The study failed to show any superiority of the sequential regimen. There were no significant differences between the two arms in the overall RR (26% versus 28%, p=0.631), TTP (Median, 7.8 versus 8.4 months, p=0.149). Toxicity profiles (grade III and IV) were equally frequent in both arms (diarrhea 13% versus 13.5%, febrile neutropenia 2% versus 1.5%, neurotoxicity 0% versus 0.5%). Conclusions: IRI-LV-5FU or IRI-LV-5FU followed by QXA-LV-5FU show equally substantial activities with manageable toxicity profile in advanced CRC. No significant financial relationships to disclose.
Allogeneic hematopoietic cell transplantation after reduced intense conditioning as adoptive cell therapy in resistant metastatic colorectal carcinoma. The European experience
Authors: Aglietta M. , Barkholt L. , Caravelli D. , Minotto C. , Capaldi A. , Omazig B. , Ciccone G. , Niederwieser D. , Ringden O. , Demirer T. 
Published: March 2020

3596 Background: Allogeneic reduced intense conditioning regimens decreased morbidity and mortality related to hematopoietic stem cell transplantation (HCT), retaining a powerful graft versus tumor effect (GVT). On this basis, it became possible to explore the existence of alloreactivity in solid tumors. A GVT effect was described in metastatic colorectal cancer (CRC). Methods: We report the data on 35 patients with CRC treated with non-myeloablative allogeneic HCT in Europe. Median time from the diagnosis of metastatic disease to transplant was 16 (4–47) months; 25 patients (67%) received at least 2 lines of therapy before transplant. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (14%) and partial response (PR) in 2 (6%). Patients were treated according to different nonmyeloablative regimens. All but one patient received allogeneic peripheral hematopoietic cells [median CD 34+ cells/kg was 6.7 × 106 (2,5–55), median CD3 + cells/kg was 4.9 × 108 (0,11–33)] from HLA identical familiar donors. GVHD prophylaxis consisted of cyclosporine A (CyA) + Mycophenolate Mofetil in 24 (68%), of CyA + methotrexate in 6 (25%) and other CyA regimens in the others (18%). Results: Myelosuppression was mild and all patients engrafted with a median donor chimerism of 90% (45–99) on CD 3 cells on day +60. Transplant-related toxicities were limited. Grades II-IV acute GVHD occurred in 18 patients (51%) and chronic GVHD in 6 patients (25%). Transplant-related mortality was the cause of death in 4 patients (11%). As best tumor response we observed: 1 complete response (3%), 8 PRs (20%) and 9 SDs (29). Overall median survival from the date of transplant was 198 days (6–1020); median overall survival for the responding patients was 353 days (113–1020). Conclusions: Allogeneic HCT after RIC is safe and feasible in metastatic CRC. The results obtained compared favorably with those observed in patients with hematologic malignancies or metastatic CRC beyond second line in terms of transplant-related complications and tumor response respectively. Thus a study of allogeneic cell therapy in a less advanced patient cohort is warranted. No significant financial relationships to disclose.
Effect of oxaliplatin-capecitabine first-line chemotherapy and tumor response on serum proteomic profiles in advanced colorectal cancer and identification of diagnostic biomarkers
Authors: Helgason H. H. , Engwegen J. Y. , Cats A. , Boot H. , Bonfrer H. G. , Beijnen J. H. , Schellens J. H. 
Published: March 2020

3603 Background: Colorectal cancer (CRC) is the third most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early diagnosis mandatory. Previously we identified serum biomarkers for CRC, by comparing serum from CRC patients and healthy controls, using SELDI-TOF mass spectrometry. Methods: We validated our identified biomarkers and assessed the effect of first-line oxaliplatin (130 mg/m2 day 1, q21)-capecitabine (1000 mg/m2 d1–14, q21) therapy by prospective standardized serum sampling at < 2 weeks prior to start of chemotherapy and serially before each chemotherapy cycle in patients with advanced CRC. Samples were drawn according to standardized protocol, centrifuged within 1 hour and stored at -30°C. After thawing they were analyzed with SELDI-TOF MS on CM10 chips at pH 5. Healthy control subjects were matched according to age, gender and time of serum collection. For serial analysis the time points T: 0, 6, 12 and 18 - 24 weeks were used. All patients had given written consent, had WHO PS ≤ 2 and measurable disease, according to RECIST criteria, and/or were evaluable by CEA. Results: In total 42 patients (mean age: 57 years; range: 37 - 73; male 62%), were treated between 06/2003 and 09/2005. All patients were previously untreated except 8 patients who had received radiation or chemo-radiation for rectal carcinoma (all > 6 months). Median follow up was 45 weeks and median number of courses was 5.5 (range: 1 -10). Response rate was 46%; PR in 19, SD in 12 and PD in 10 patients, respectively (1 not evaluable) and median overall survival was 10.5 months. We identified 6 peptides/proteins (m/z: 31948, 8078, 28101 (apolipoprotein A-I), 7970, 5912 and 12861 Da, respectively (in order of significance) discriminating between CRC and healthy controls (p < 0.001). In a serial analysis of the patients a peptide, with m/z: 5.9-kDa (most likely fibrinogen split product) declined, during chemotherapy in some responsive patients, but apolipoprotein A-I appeared not to change. Conclusions: We confirmed our previous identification of apolipoprotein A-I (m/z: 28-kDa) as a potential biomarker for CRC and suggest a peptide with m/z: 5.9-kDa as a potential biomarker of response. No significant financial relationships to disclose.
Molecular signatures generated with RNA isolated from formalin-fixed paraffin-embedded tumor specimens differentiate metastatic and non-metastatic primary colorectal cancer
Authors: Shimizu D. , Kuramochi H. , Tanaka K. , Cooc J. , Xiong Y. , William M. , Li R. , Danenberg K. D. , Danenberg P. V. , Lenz H. J. 
Published: March 2020

3615 Background: Colorectal cancer (CRC) can be either non-metastatic (locally-advanced) or metastatic, with the latter having a considerably worse prognosis. Because tissue from patients is generally available only as FFPE specimens, we investigated whether distinct molecular signatures could be obtained for these CRC types using RNA isolated from archival FFPE specimen blocks in gene expression arrays. Methods: FFPE specimens were available from 12 non-metastatic tumors and 9 primary tumors along with their matching metastases. Up to 5 10-micron sections of each were microdissected to isolate areas of tumor tissue. RNA was extracted using a proprietary procedure of Response Genetics, Inc. and was then amplified and labeled. The resulting cRNA was hybridized to the U133 plus 2.0 GeneChip. Unsupervised PCA analysis of the samples resulted in the first principal component separating 2 distinct groups, which consisted of the non-metastatic and metastatic tumors. A differentially expressed gene list between metastatic and non-metastatic CRC was determined. These data were also analyzed for differential canonical pathways using Ingenuity Pathway Analysis. Results: Hierarchical clustering analysis segregated locally advanced primary tumors and metastatic primary tumors into two clusters with distinct gene signatures. A T-test with unequal variance assumption identified 609 differentially expressed probe sets with FDR (false discovery rate) = 0.05. Comparison of primary tumors with their liver metastases using a paired T-test showed only 2 differentially expressed genes at FDR = 0.05 but 526 genes with significance p value < 0.005. Pathway analysis showed significant deregulation of VEGF, hypoxia, B Cell receptor, PI3K/AKT, ERK/MAPK and G-protein coupled receptor signaling between locally advanced and metastatic tumors. Pathway analysis of primary tumors and metastases showed deregulated TGF-b, integrin and chemokine signaling pathways. Conclusion: We have demonstrated the feasibility of identifying metastatic and non-metastatic tumors by microarray analysis using FFPE CRC tissue. This result is currently being validated in a separate larger cohort of patients. [Table: see text]
Fecal mutational load and distribution analysis in the non-invasive diagnois of colorectal cancer
Authors: Tarafa G. , Blanco I. , Casadomé L. , Mora F. , Vilardell F. , Moreno V. , Lizardi P. , Costa J. , Capellá G. 
Published: March 2020

3618 Background: Specific molecular profiles of exfoliated tumour cells may lead to non invasive diagnosis of cancer. We have developed a DNA chip-based methodology that allows for the simultaneous and quantitative detection of multiple allelic substitutions in bodily fluids. Total Mutational Load Distribution Analysis (MLDA) of DNA found in bodily fluids yields biometrics that may enable early tumor diagnosis. We wanted to ascertain whether the MLDA of selected K-ras and p53 mutations in fecal DNA distinguishes between absence of tumor and the presence of neoplastic disease and whether patients with adenomas can be distinguished from those bearing carcinomas. Method: DNA was obtained from solid stools or colonic lavage in 67 patients undergoing colonoscopy: non-neoplastic condition (n=24); adenomas (n=16); carcinomas in situ (n=6) and carcinomas (n=21). Quantitative and simultaneous detection of 8 substitutions at codons 12 and 13 of K-ras gene and 15 hotspots substitutions at exons 5 and 7 of p53 gene was performed using an oligonucleotide zip-code microarray with rolling circle amplification signal enhancement. Total Mutational Load (TML) and relative prevalence values of independent alleles were measured. Results: MLDA separated the three groups: Total Mutational Load (TML) of non-neoplastic conditions ranged from 5.3 to 7.15. TML of adenomas ranged from 16.50 to 22.24 and of carcinomas in situ from 22.30 to 36.29. TML of invasive carcinomas ranged from 25.06 to 67.9. In a training set of the first 40 samples analyzed a halfway cut-off value of 11.87 was established to discriminate between non-neoplastic and neoplastic disease. Sensitivity was 100% (95% CI 91.7–100) and specificity was 100% (95% CI 86.2- 100) in both sets. We have reproduced similar results with classic techniques like sequences and cloning. Conclusion: Stool MLDA appears to be a useful non-invasive marker of distal and proximal colonic neoplasms that deserves widespread validation. No significant financial relationships to disclose.
Assessment of the role of Fanconi Anemia (FA) genes in colorectal cancer: A new pathogenetic pathway?
Authors: Palmieri G. , Colombino M. , Camboni M. G. , Manca A. , Baldinu P. , Izzo F. , Tatangelo F. , Calemma R. , Cossu A. , Galimi F. 
Published: March 2020

3629 Background: Fanconi Anemia (FA) is an autosomal recessive disease marked by congenital defects, bone marrow failure, and high incidence of leukemia and solid tumors. Eight FA associated genes have been cloned, and their products are thought to function in an integrated pathway which includes BRCA genes and maintains genomic stability. A molecular mechanism involved in the development and progression of some human malignancies, including colorectal cancer, is represented by a defective replication fidelity. Here we tested the role of the main FA genes in colorectal cancer (CRC). Methods: One hundred consecutively-collected patients with histologically-proven diagnosis of CRC and no mutation in the main mismatch repair genes (MLH1 and MSH2) were included into the study. Genomics DNA was screened using DHPLC for FANC-C/G/E/F genes and using MPLA for FANC-A/D2 genes. All PCR products with abnormal DHPLC profiles were sequenced on an automated sequencer. For 28 cases, tumor tissue samples were also analyzed. To date, total RNA was isolated from paired normal and tumor samples of 12 CRC patients. Gene expression was quantified by real-time RT-PCR using the Taqman approach. Results: At germline level, 2 cases presented FANC-C sequence variations (Asp267Ser, Val449Ser) and 5 cases showed a exon 26 deletion in FANC-A as detected by MLPA analysis. Among the 28 tumor samples available from patients negative for mutations in germline DNA, 2 (7%) cases presented a FANC-E mutation (Ala552Thr). Moreover, one of such somatic samples presented a BRCA2–8765delAG mutation (BRCA2 is also recognized as FANC-D1 gene). Assuming as significant difference in gene expression the presence of a variation of more than 50% in mRNA levels between normal and corresponding tumor samples, all tested FA genes (FANC-C/G/E/F) were found overexpressed in 5/12 (42%) tumor samples. Conclusions: Although preliminary, our findings seem to identify a subset of CRC patients with alterations in the FA/BRCA pathway which is required for the activation of DNA repair. Ongoing molecular analyses will better clarify the real frequency of each alteration in FA genes and their relationship with the histological and/or clinical features in colorectal cancer. No significant financial relationships to disclose.