bluuebunny/crossref_metadata_2025_split huggingface dataset:
ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases, blocks VEGF-C-induced activation of VEGFR-3 and cell proliferation in human colon cancer cell lines
Authors: Troiani T. , Lockerbie O. , Morrow M. , Ciardiello F. , Eckhardt S. G. 
Published: March 2020

13171 Background: Vascular endothelial growth factor receptors 1, 2 and 3 (VEGFR-1, -2 and -3) have a key role in activation and proliferation of endothelial cells, with expression of VEGFR-3 largely restricted to lymphatic endothelial cells. Although high expression of VEGFR-3 and its specific ligands, VEGF-C and VEGF-D, has been associated with an increased incidence of lymph node metastasis and a poor prognosis in different human malignancies, little is known about the role of this signaling pathway in tumor cells. This study investigated VEGFR-3 and its specific ligands in human colon cancer cells, and the antiproliferative activity of ZD6474, an inhibitor of VEGFR, epidermal growth factor receptor (EGFR) and RET tyrosine kinases, and of the EGFR inhibitors gefitinib and cetuximab. Methods: The expression of VEGFRs and EGFR was determined by RT-PCR, immunoblotting, flow cytometry and immunohistochemistry in four human colon cancer cell lines (HCT-116, HT-29, HCT-15 and SW480). Secretion of transforming growth factor-α (TGF-α), VEGF-A and VEGF-C by cancer cells was determined by ELISA. The in vitro antiproliferative effects of ZD6474, gefitinib and cetuximab were determined using an MTT assay. Results: All four human colon cancer cell lines expressed functional EGFR and secreted high levels of TGF-α. All four cell lines expressed VEGFR-1 and VEGFR-3, but not VEGFR-2, and secreted both VEGF-A and VEGF-C. Treatment with ZD6474 resulted in a dose-dependent cell growth inhibition (IC50 3–5 μM), whereas treatment with gefitinib or with cetuximab produced little growth inhibition under the same culture conditions. Addition of VEGF-C induced a 2-fold increase in cell growth in vitro in all four colon cancer cell lines. Treatment with ZD6474 blocked both basal and VEGF-C-induced phosphorylation of VEGFR-3, as well as VEGF-C-induced cell proliferation. Conclusions: Human colon cancer cell lines express VEGFR-1 and VEGFR-3, and secrete VEGF-A and VEGF-C. A potential VEGF-C/VEGFR-3 autocrine loop has been identified in human colon cancer cells, which can be inhibited by ZD6474, suggesting that ZD6474 may have direct antitumor activity through inhibition of VEGFR signaling. [Table: see text]
Results of a phase II trial of cetuximab+XELIRI as first-line therapy of patients with advanced and/or metastatic colorectal cancer
Authors: Cartwright T. H. , Kuefler P. , Cohn A. , Hyman W. , Boehm K. A. , Ilegbodu D. , Asmar L. 
Published: March 2020

13502 Background: We have previously shown that capecitabine/irinotecan (XELIRI) is effective and well-tolerated in metastatic colorectal cancer (mCRC). Cetuximab targets EGFR and is active in mCRC either alone or combined with chemotherapy. This study evaluated potential improved outcomes with cetuximab+XELIRI in first-line treatment of mCRC. Subjects and Methods: Subjects had histologically confirmed colorectal adenocarcinoma with T4 lesions that were deemed unresectable after preoperative chemoradiation and/or metastatic disease. Treatment: capecitabine 1700 mg/m2 (850 mg/m2 PO BID Days 1–14), irinotecan 200 mg/m2 IV Day 1 every 3 weeks, and weekly cetuximab (initial dose 400 mg/m2 IV over 120 minutes, subsequent doses 250 mg/m2 over 30 minutes). Toxicity was assessed at each visit. Results: Between February and October 2005, 70 subjects enrolled. Baseline characteristics: 43 males (61%), 79% White, median age 61.5 years (range, 32.2 - 85.4), and ECOG PS 0/1= 66%/34%. 63% of subjects had Stage IV disease at diagnosis; 87% of subjects had adenocarcinoma. Prior therapy: surgery (n=60, 86%), chemotherapy (n=14, 20%), and radiotherapy (n=5, 7%). Grade 3–4 treatment-related toxicities in >1 subject included diarrhea (17%); neutropenia and rash (8.5% each); dehydration (7%); nausea/vomiting (5%); and anorexia, dyspepsia, and hypokalemia (3% each). 30 subjects discontinued due to progressive disease (PD) (n=9), toxicity (n=12), MD decision (n=2), patient request/withdrew consent (n=3), death (n=1) and other (n=3; doses delayed >3 weeks). To date 5 subjects have died; no death was treatment-related. Evaluation of tumor responses is ongoing. Conclusions: The combination of cetuximab+XELIRI is feasible and well-tolerated in first-line mCRC. Updated safety and efficacy data will be presented. Funded in part by Bristol-Myers Squibb, Plainsboro, NJ. [Table: see text]
Cost-effectiveness of adjuvant capecitabine, Mayo Clinic and de Gramont regimens for stage III colon cancer in the French setting
Authors: Dufour P. R. , Douillard J. , Ychou M. , Seitz J. , Perrocheau G. , Tilleul P. , Maes P. , Husseini F. 
Published: March 2020

13506 Background: The oral fluoropyrimidine capecitabine is as effective but better tolerated than i.v. 5-FU/LV as first-line treatment in patients (pts) with metastatic colorectal cancer. Costs associated with the administration route could vary widely according to national rules and medical practice. We compared costs and outcomes of capecitabine, the Mayo Clinic, and de Gramont regimens as adjuvant treatment for stage III colon cancer. Methods: We assessed the cost-effectiveness of the three regimens using the third-party payer perspective, time horizon and efficacy/safety data (adjusted for indirect comparisons) from two published clinical trials [Twelves et al. N Engl J Med 2005; Andre et al. J Clin Oncol 2003]. The costs of chemotherapy and the treatment of side effects were estimated from the clinical trials and expert opinion. We applied French standard costs to resources consumed and evaluated cost-effectiveness using relapse-free survival (RFS), defined in X-ACT study, as an efficacy indicator. One-way sensitivity analyses were performed varying the cost estimates for each treatment. Results: Capecitabine-treated pts had a mean life duration increase without treatment failure of 1.3 months vs. Mayo (see table). De Gramont was considered as effective as Mayo. In the base-case analysis capecitabine appeared to be dominant, more effective and less costly than either Mayo Clinic or de Gramont. In the sensitivity analyses, capecitabine remained dominant except for the minimum costs scenario vs. de Gramont. In this case, the cost-effectiveness ratio was estimated at 8997.55€ per year without relapse. Conclusions: As adjuvant treatment for colon cancer, capecitabine decreases medical resources consumed, mainly in hospitals. Its approval in this setting is expected to bring cost savings and better outcomes. [Table: see text] [Table: see text]
A phase I clinical and pharmacokinetic study of flavopiridol administered concurrently with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced solid tumors
Authors: Meng R. D. , Carvajal R. D. , Tse A. N. , Shah M. A. , Dials H. , Brukner D. , O’Reilly E. M. , Kelsen D. P. , Schwartz G. K. 
Published: March 2020

13515 Background: Flavopiridol, a potent cyclin-dependent kinase inhibitor, enhances oxaliplatin-induced apoptosis in HCT116 colon cancer cells in vitro, especially with concurrent therapy. Significant tumor regressions were also observed in HCT116 xenografts treated with flavopiridol and oxaliplatin therapy versus either therapy alone. Methods: Therefore, an ongoing phase I trial in advanced solid tumors was designed in which flavopiridol at a fixed dose (40 mg/m2 over 1 hour) was administered concurrently with escalating doses of oxaliplatin (60 mg/m2 -> 80 mg/m2 over 2 hours), given as part of a modified FOLFOX6 regimen at standard doses every 14 days. Patients then received escalating doses of infusional 5-fluorouracil over 48 hours (900 mg/m2/day -> 1200 mg/m2/day). Standard phase I eligibility criteria apply. Prior FOLFOX or oxaliplatin was allowed. Results: Median characteristics of nineteen evaluable patients: age 54 (39–77), KPS 80% (70–90), 9 males/10 females, 3 prior regimens (range 1 to 10). The combination has been well-tolerated, with 1 dose limiting toxicity occurring with oxaliplatin at 85 mg/m2 and infusional 5-fluorouracil at 1200 mg/m2/day (grade 3 hyponatremia and grade 3 syncope). Pharmacokinetic studies for flavopiridol indicate no appreciable difference in Cmax despite escalation of oxaliplatin dose. We have observed 1 partial response to treatment in pancreatic cancer. Stable disease has been seen in 5 patients, including 1 breast cancer (3 months), 1 gastric cancer (2 months), 1 anal cancer (7 months) and 2 colorectal cancers (5+ months), with one patient previously treated with oxaliplatin. Conclusions: The combination of flavopiridol and modified FOLFOX6 can be given safely without a significant increase in toxicity. The pharmacokinetic data for flavopiridol remains unchanged despite escalating doses of oxaliplatin. Activity has been observed in several tumor types, with promising activity noted for colorectal cancers even with prior oxaliplatin chemotherapy. Therefore, further dose escalation of flavopiridol is currently planned. No significant financial relationships to disclose.
Cetuximab use without chronic antihistamine premedication
Authors: Timoney J. , Chung K. Y. , Park V. , Trocola R. , Peake C. , Saltz L. B. 
Published: March 2020

13521 Background: Cetuximab is a human-murine chimeric monoclonal antibody against EGFR with approximately a 3% reported incidence of severe (≥ grade 3) anaphylactoid reactions. The overwhelming majority of such reactions have been reported with the initial dose of cetuximab. Diphenhydramine (Benedryl)or a related antihistamine is often given as a premedication for cetuximab, however this may cause fatigue or other side effects. Most early clinical trials of cetuximab permitted investigator discretion in use of premedication beyond the initial cetuximab dose. Methods: We obtained an IRB waiver of authorization to review the records of patients treated with cetuximab at Memorial Sloan Kettering Cancer Center for the first year of commercial availability of cetuximb (Feb, 2004 through Feb, 2005). Computerized pharmacy records were reviewed to identify all patients who were treated with cetuximab (outside of a clinical trial) and use of premedication was then evaluated. Records of institutional adverse event reports regarding chemotherapy administration were reviewed, and, any moderate or severe/life-threatening reactions were evaluated for presence or absence of concurrent premedication. Results: As per our institutional guidelines, all patients received 50 mg of diphenhydramine prior to the initial loading dose of cetuximab, and 25 mg of diphenhydramine prior to the second dose. While there was inconsistency in terms of cessation of diphenhydramine, overall a total of 115 patients received one or more doses of cetuximab without premedication. A total of 746 doses of cetuxmab without diphenhydramine premedication were given over this time period. No severe/life-threatening reactions to cetuximab occurred during these doses given without premedication. Conclusions: Omission of diphenhydramine premedication after the initial two doses of cetuximab is our current institutional practice, and appears not to alter the safety profile of cetuximab. Considering the side effects of diphenhydramine, routine long tern use of antihistamine premedication with cetuximab administration does not appear to be warranted. [Table: see text]
Implementation of 18F-FDG PET/CT in the management of colon cancer
Authors: Manente P. , Chierichetti F. , Liessi G. , Sartor L. , Vicario G. , Bissoli S. , Medea S. , Scelzi E. , Mion M. 
Published: March 2020

13526 Background: we began using PET in 1994 and since the beginning of 2000 we started with a PET/CT system. Aim of our study was to evaluate if PET/CT is a decision making tool in patients with a history of colon tumors. Methods: we performed PET/CT in 26 patients, 14 males and 12 females (mean age 60.9, range 42–75 years) already treated for a colon cancer. Each patient was submitted to two PET/CT scans in a period of 5–11 months. PET/CT was performed using 18F-FDG as radiopharmaceutical. In all patients other examinations were perfomed, such as liver ecography, pelvis MRI and CT scan. Results: in the first PET/CT imaging, 11/26 patients presented with normal tumor markers but suspected relapse on the basis of CI, 7/26 had increased markers but negative CI, the other 8 patients had both CI and tumor markers meaningful for recurrence. 7/26 PET/CT were normal: 5 cases with negative tumor markers but positive CI and 2 patients with increased CEA levels. Among the 19/26 positive PET/CT scans, 7 patients had normal marker levels. All positive PET/CT patients were treated and, at the second examination, progressive disease was evident in 11 out of 19. For the 7 previous negative PET/CT, the second findings showed tumor recurrence in 2 patients, but PET/CT became negative in 5 previously positive cases, submitted to surgery and/or chemotherapy. This method detected relapse in 73% of the patients and, during the follow up, it was sensitive to identify progressive disease or to prove treatment’colon cancer, based on tumoral marker assays and CI, is poorly sensitive to detect relapse. Our PET/CT data show that 37% of cases with normal marker levels have a recurrent disease. The overall results of our preliminary data lead to further considerations: 1) PET/CT gives a precise localization of lung or nodal metastases and local relapse; 2) the repeated PET/CT scan is reliable also to evaluate the effect of therapies; 3) this imaging modality may be crucial to detect relapse, but more data are needed to assess the proper time to perform PET/CT in the follow up to have a real gain in life expectancy. No significant financial relationships to disclose.
A phase I/II study of capecitabine (X), irinotecan (I) and oxaliplatin (O) as first-line therapy in patients (pts) with advanced or metastatic colorectal cancer (MCRC)
Authors: Maroun J. A. , Jonker D. , Goel R. , Cripps C. , Lister D. , Chiritescu G. 
Published: March 2020

13540 Background: Triplets of I, O and infusional 5-FU/Leucovorin (LV) are associated with high response rates and long survival in first-line MCRC [Falcone et al. JCO 2002;20:4006–14]. The oral fluoropyrimidine X has proved higher response rates and improved safety vs. 5-FU/LV in MCRC. Methods: This ongoing dose-escalation study aims to establish dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase II doses (RPIID) of I and O in combination with X as first-line therapy for MCRC and to assess the efficacy and safety of this XIO combination. Starting doses were: I (180mg/m2 i.v. on day 1), O (85mg/m2 i.v. on day 1), and X (850mg/m2 bid orally on days 2–15). Dose escalations are based on toxicity observed at the previous dose level (DL), until DLT, MTD and RPIID are documented, at which time a phase II component begins. Results: We enrolled 18 pts (13 men, 5 women), median age 61 (range 44–74) at 4 DLs. ECOG PS was 0 or 1 in 17 pts, and 2 in 1 pt. Pts received a median of 7 cycles (range 1–15) of XIO. All pts are evaluable for toxicity and 14 for response. The most common adverse events were: neutropenia (83% all grades (G) with 4 G3, 4 G4), diarrhea (67%, 4 G3, one of which was a DLT). Nausea (78%) and vomiting (56%) were mild and controlled with anti-emetics. Fatigue occurred in 50% pts, with 1 G3. The DLT was febrile neutropenia (3 pts at DLs 1, 3, & 4 respectively). One pt at DL4 developed severe neutropenia and sepsis during cycle 3, had aspiration pneumonia and died in hospital from respiratory and cardiac complications. MTD has not yet been reached. Responses were observed at all DLs: 11 partial responses with 2 still unconfirmed (79%, 95% CI 54–100), and 2 stable disease (14%). Progression-free survival and overall survival have not been reached. Conclusions: XIO is well tolerated and demonstrated significant efficacy as first-line treatment in MCRC. Severe neutropenia was significant but was of short duration and manageable. It is likely to be the main DLT. MTD has not yet been identified but is expected in the next few pts. A phase II study to confirm the efficacy and safety of the XIO combination will follow. Supported by Roche, Sanofi Aventis, and Pfizer Canada Inc. [Table: see text]
Multicenter phase II study of cetuximab and irinotecan as third line chemotherapy in patients (pts) with metastatic colorectal cancer (MCRC) previously treated with both irinotecan and oxaliplatin regimens
Authors: Grande C. , Mel J. R. , Salgado M. , Reboredo M. , Candamio S. , Fernandez I. , Quintero G. , Huidobro G. , Firvida J. L. , Valladares M. 
Published: March 2020

13551 Background: Pts with chemotherapy-resistant MCRC have a really poor prognosis with few therapeutic options. Cetuximab (Erbitux®) is an IgG1 monoclonal antibody targeting the EGFR, shown to be effective in pts with EGFR-expressing MCRC refractory to prior irinotecan-based chemotherapy (Cunningham NEJM 2004). Methods: The goal of this multicenter phase II study is to investigate the safety and efficacy of cetuximab in combination with irinotecan as third line treatment in 40 pts with heavily pre-treated MCRC. From Jan to Dec 2005, 40 pts with EGFR-expressing MCRC, refractory to irinotecan, pre-treated with both irinotecan and oxaliplatin with fluorouracil or capecitabine combinations, and PS 0–2, were included to receive cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus irinotecan (180 mg/m2 every 2 weeks) until tumour progression or unacceptable toxicity. Pts were analysed weekly for toxicity and every 12 weeks for response. Recruitment is completed. Currently, 38 pts are evaluable for toxicity (2 pts recently recruited) and 23 pts for response (16 pts on treatment for <12 weeks and 1 pt withdrew at week 6 due to lung thromboembolism not related to study treatment). Results: M/F 24/14, median age 63 years (range: 33–78), colon/rectum 23/15, ECOG PS=0/1/2 9/23/6, Metastatic sites 1/2/>2 16/19/3 (Liver 43%, lung 23%, nodes 17%, pelvic 5%, others 12%). A total of 418 weekly infusions were administered (mean: 11; range: 3–37). Preliminary efficacy data is as follows: 3 PR, 3 SD, 17 PD with an overall response rate of 13% (95% CI: 3–34%) and disease control rate of 26% (95% CI: 10–48%). Major toxicities (G 1–2/G 3–4) were: Acne-like skin rash 58/11%, Anemia 32/3%, Neutropenia 16/13%, Nausea-vomiting 32/0%, Diarrhoea 32/11%. Median time to progression was 3.5 months (Range: 1–10+) and median overall survival was 7.3 months (Range: 1.5–12+). Conclusions: These preliminary results suggest that cetuximab and irinotecan combination, is a reasonably effective treatment for pts with highly pre-treated MCRC with an acceptable toxicity profile No significant financial relationships to disclose.
Impact of the size of metatases on the outcome of patients with non-resectable colorectal liver metastases treated with percutaneous laser-induced thermoablation (pLIT)
Authors: Aprile Esq. G. , Sponza M. , Vit A. , Pella N. , Gasparini D. , Zanon E. , Iaiza E. , De Pauli F. , Marzio A. , Piga A. 
Published: March 2020

13556 Background: whenever surgical resection of liver metastases from colorectal cancer is not possible, thermal ablation is a mini-invasive local treatment that can be considered as an alternative approach. Complete thermal ablation can be achieved by laser treatment. When thermoablation is obtained by radiofrequency, patients treated for a small dominant lesion (less than 3 cm) experience a better outcome. This evidence is less clear when pLIT is used. Patients and Methods: 30 patients (22 with a single lesion, 8 with up to three metastases) were consecutively treated. Maximum diameter of the dominant lesion was less than 3 cm in 20 pts and more than 3 cm in ten. With mild sedation and local anaesthesia, optical fibers were inserted directly into the tumor with echo-guided percutaneous needle placement. Each optical fiber was connected to a neodymium:yttrium-aluminium-garnet (ND:YAG) laser, which delivers concentrated light at a wave-length of 1064 nm, with a 5-Watt power and a 1800-Joule energy per single fiber. A minimum of two and a maximum of four needles were used, with a 5 to 8 mm distance from one needle to another. Results: all patients tolerated LIT procedure well, without major complications. Post-treatment CT-scan demonstrated complete thermonecrosis in 39 out of 44 (87%) of the treated lesions, and almost complete in the remaining 5, 4 of which of diameter larger than 3 cm. Local failure was reported in 12% of the lesions at six-month follow-up. The median Kaplan-Meier survival for all patients was 607 days, with survival rate of 82% at one year and 55% at three years. Patients treated for a smaller dominant lesion had a significantly better survival than the others (850 vs 420 days, p=0.04, logrank). Conclusions: pLIT permitted in most cases a complete ablation of liver metastases with a high local tumor control rate and a low complication rate. Patients with a smaller dominant lesion do best after pLIT procedure. Local treatment coupled with systemic chemotherapy offers a chance of prolonged survival in patients not amenable to hepatic surgery. No significant financial relationships to disclose.
Pharmacokinetics of Irinotecan and SN38 after intra-arterial liver perfusion according to infusion time and circadian patient pattern in metastatic colorectal cancer
Authors: Pirovano M. , Nasisi A. , Paraboni L. , Sestini S. , Masseroni S. , Gherardi F. , Martignoni G. , Meregalli M. , Fornasari D. , Scaglione F. , Tabiadon D. 
Published: March 2020

13557 Chronotherapy studies in pretreated CRC cancer pts showed that 6 hrs chronomodulated CPT11 infusion from 2 to 8 a.m., alone or combined with 5FU+AF±OHP, is less toxic than the standard 90 min. infusion, and CPT11-SN38 convertion efficency is improved with an higer objective response rate. Objective of this study was evaluation of CPT11 pharmacokinetics after hepatic i.a. perfusion according to infusion time and circadian patient pattern. To evaluate patient circadian pattern, serum levels of prolactin and cortisol were detected at 2–6, 4 pm and 2–6, 4 -8 pm respectively. CPT11 and SN38 serum levels were detected, according to two different time schedules, following the HPLC method. Every pt received 240 mg/mq i.a. CPT11 perfusion alternating daily with nightly schedule: from NOV04 to FEB05 5 metastatic CRC patients were treated. All pts concluded all programmed cycles. No cycle was delayed due to toxicity. Haematological, hepatic and g.i. G 3–4 (NCI) toxicity were not observed (only neutropenia G1 in the female subject). Circadian organization seems to be progressively lost according to cycle number. At 3rd cycle, cyrcadian levels of cortisol and prolactin are lost in all pts. Kinetic data suggests for a progressive reduction of liver enzymatic capability; this is probably due to cumulative liver drug toxicity: this phenomenon is clearly evidenced in female subject but is also signicative in the male subjects (see Table). These preliminary data show enormous PK/PD interpatient variability and a significative AUC reduction 2nd cycle vs 1st and 3rd vs 2nd; due to this unespected observation we are not able to evaluate cyrcadian oscillation of enzymatic systems: in order to fully understand these data we decided to perform polimorphism assesment for UGT1A1,Carboxil Esterase isoform2 and ABC transporters genes.This analysis will be performed on paraffin included samples for the first 5 pts and on fresh tissue for the next pt set. [Table: see text] No significant financial relationships to disclose.