bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apoptosis signal ceramide c6 synergizes anti-tumor effects of paclitaxel oxaliplatin & cisplatin on growth of pancreatic cancer in SCID mice
Authors: Shrayer D. , Wanebo H. J. , Resnick M. 
Published: March 2020

13135 Background: Ceramide (C6) is an analog of endogenous ceramides, which are a major signaling pathway for apoptosis in cells undergoing stress, exposure to chemotherapy. Current report documents in vivo anti tumor effects combining C6 with oxaliplatin & cisplatin on L3.6 human pancreatic adenocarcinoma implanted in the SCID mouse. Correlative histologic studies provide additional mechanistic insights. Methods: SCID/Beige/ Taconicmale mice were inoculated subcutaneously (S.C.) w/2×106 L3.6 pancreatic cells. Chemotherapy doses were based on clinical & in vitro data. Treatment began 4 days post tumor implant with 3 weekly 3×/wk) intraperitoneal (IP) injections of Paclitaxel (P) 3.0 m/kg, oxaliplatin (OX) 2.5 mg/kg, cisplatin (CP) 2.5 mg/kg, with/without ceramide 10 mg/kg. Mice were observed for 6 weeks & were autopsied when near death, or at 6 week level. (All controls died by 3rd week). Data recovered included maximum tumor volume, tumor weight, body weight & survival. Histopathology studies were carried out in a separate group of 40 mice treated by the same drug dose levels & autopsied at 4 hours & 24 hours. Tumors were bi-valved & fixed in buffered formalin or frozen in hexane/acetone bath. Major focus was effects on tumor necrosis, apoptosis, mitotic index & Apoptosis (caspase 3 expression) index. Results: Combination w/C6 ceramide augmented the tumor reduction obtained by chemotherapy alone by 57% (while preserving body weight), & increased 6 wk survival from 0% (Chemotherapy alone) to 60% w/combined therapy. Mean survival was increased from 25 to 37 days. Preliminary short term immunohisto chemical studies showed enhancement of apoptotic index by increased and caspase 3 expression at 4 & 24 hr by ceramide combinations. Conclusion: Combination therapy w/C6 Ceramide significantly enhanced anti tumor response to Paclitaxel, Oxaliplatin & Cisplatin in SCID Mice bearing L3.6 pancreatic tumor implants. Early development of enhanced apoptosis by caspase 3 expressions was shown in preliminary short term exposure experiments. No significant financial relationships to disclose.
NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, prevents breast cancer metastasis in vivo
Authors: Kawahara E. , Ohmori O. , Nonomura K. , Murakami Y. , Tomioka D. , Niwa S. , Meyer T. , Mestan J. , Honda T. , Hatakeyama S. 
Published: March 2020

13163 Background: Focal Adhesion Kinase (FAK) and Insulin-like Growth Factor-1 Receptor (IGF-IR) kinase are attractive anti-cancer drug targets because they are both drivers of tumor cell proliferation, migration, and survival. Although virtually every cell type expresses FAK, it is generally overexpressed in tumor cells. FAK levels are greatest in highly metastatic tumors. A selective FAK inhibitor would be expected to halt or kill invasive tumor cells, and potentially interfere with normal cell migration (e.g. endothelial cells). IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: NVP-TAE226, a novel small molecule developed as an inhibitor of FAK, was evaluated in kinase enzymatic assays, cell-based kinase assays and 4T1 metastatic breast carcinoma in vivo model. Results: NVP-TAE226 inhibits FAK with low nanomolar IC50 values in a purified kinase enzymatic assay. In cell-based kinase assays, FAK and IGF-IR kinase were inhibited with an IC50 range of 100 to 300 nM compared to the other kinases tested which were >10-fold less sensitive. Oral administration of NVP-TAE226 inhibited 4T1 murine breast tumor growth and metastasis to the lung in a dose-dependent manner. The compound was well tolerated in mice as determined by measuring changes in body weight. The highest dose of 100 mg/kg, qd, 5x/week showed T/C value of 18%. Inhibition of FAK autophosphorylation at Y397 and Akt phosphorylation at Serine473 was observed in a dose-dependent manner in 4T1 breast carcinoma. Conclusions: NVP-TAE226 represents a novel class of selective and small molecule kinase inhibitors that have potential clinical applications with a potent in vivo activity. [Table: see text]
Antitumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases
Authors: Morelli M. P. , Cascone T. , Troiani T. , Tuccillo C. , Bianco R. , Romano M. , Eckhardt S. G. , De Pacido S. , Tortora G. , Ciardiello F. 
Published: March 2020

13170 Background: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 (ZACTIMA™) is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the antitumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells. Methods: The antitumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: In vitro, the combination of ZD6474 and cetuximab produced synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In vivo, 4 weeks of treatment with ZD6474 (75 mg/kg p.o., days 1–5 each week) or cetuximab (1 mg i.p., days 2 and 5 each week) produced a tumor growth delay of 21–28 days (P < 0.001) in nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) cancer xenografts compared with untreated controls. Combination treatment with ZD6474 and cetuximab for 4 weeks resulted in a more marked tumor growth delay of 120–140 days compared with controls, and this was significantly greater than with either single agent therapy (P < 0.001). Following combination treatment, 3/10 A549 xenograft-bearing mice and 4/10 GEO xenograft-bearing mice had no histologic evidence of tumor at the end of the experiment. Immunohistochemical analysis of tumor samples obtained from mice treated with the two drugs in combination demonstrated a cooperative inhibition of cancer cell proliferation and an almost complete suppression of tumor angiogenesis. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy. [Table: see text]
Capecitabine (X) vs. bolus 5-FU/LV as adjuvant chemotherapy for patients (pts) with Dukes’ C colon cancer: economic evaluation in an Italian hospital setting
Authors: Di Costanzo F. , Sobrero A. , Twelves C. , Douillard J. , Giuliani G. , Patel K. , Garrison L. P. , Cassidy J. 
Published: March 2020

13518 Background: In the X-ACT adjuvant trial, X showed consistent benefits over bolus 5-FU/LV, with at least equivalent disease-free survival (DFS) and an improved safety profile [Twelves et al. 2005]. In addition, X demonstrated superior relapse-free survival (65.5% vs. 61.9% at 3 years follow-up; p=0.0407) and improved covariate-adjusted overall survival (p=0.0208). We used the results from X-ACT to assess the cost-effectiveness of X from the Italian hospital and societal perspective. Methods: Trial-based data were collected on treatment period medical resource use. Unit costs for drug administration, hospitalizations, emergency room visits, and concomitant medications were considered using published sources in Italy. Cost for physician consultation visits, pt time and travel were also considered in the societal perspective. A health-state transition model was used to estimate incremental cost impact and the effectiveness in terms of gains in quality-adjusted life months (QALMs). Costs and effectiveness were discounted at 3.5%. Results: Mean duration of treatment was similar with X and 5-FU/LV; pts received 92% and 93% of planned treatments, respectively. Administration of X required fewer clinic visits per pt (7.4 vs. 28.0 with 5-FU/LV). Acquisition costs of X were higher than 5-FU/LV, approximately 2533 vs. 231€, but this difference was more than fully offset by the difference in administration cost of 5-FU/LV (4338 vs. 152€ for X). Total hospital days for treatment-related adverse events (AEs) and medication costs for treating AEs were higher for 5-FU/LV than X. The cost of emergency room visits for treating AEs and physician consultation did not differ. Compared with 5-FU/LV, X is projected to increase QALMs by 6.5 months, with overall treatment period cost savings of 2234€ for the hospital. From a societal perspective, the cost savings increase to 3976€. These findings show that X is a dominant (cost-saving and more effective) treatment in this setting. Conclusions: X as adjuvant treatment for pts with colon cancer is clinically effective with an improved safety profile vs. 5-FU/LV and is also a dominant choice from an economic perspective. [Table: see text]
Gefitinib and irinotecan in patients with fluoropyrimidine-refractory irinotecan-naïve advanced colorectal cancer (CRC): dose-finding, pharmacokinetics, safety and efficacy
Authors: Hickish T. , Chau I. , Massey A. , Higgins L. , Osborne R. , Botwood N. , Swaisland A. , Cunningham D. C. 
Published: March 2020

13520 Background: Gefitinib (IRESSA) is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown supra-additive activity in human CRC xenografts when combined with irinotecan. We have previously established that the recommended dose level (RDL) to be irinotecan 225mg/m2 q3 weeks and gefitinib 250mg daily (Chau et al ASCO 2004). The dose limiting toxicities were neutropenia and diarrhoea. The continuation phase of this study aimed to evaluate the efficacy and safety of this combination. Patients and Methods: Between Jun 2002 and Feb 2005, patients (pts) with advanced CRC progressing on or within 12 weeks of fluoropyrimidines-based chemotherapy, irinotecan-naïve and performance status ≤2 were recruited. Thirty-nine pts were treated with irinotecan and gefitinib in total with 27 treated at the RDL. Results: Median age was 61 years (range: 31–79) and 13 (33.3%) pts were females. All pts were Caucasians (94.9%) and non-oriental Asians (5.1%). Thirteen (33.3%) pts had received (neo)adjuvant chemotherapy and 16 (41.0%) pts had prior oxaliplatin-based chemotherapy for metastatic disease. Grades 3–4 toxicities were anaemia 2.6%, neutropenia 15.4%, febrile neutropenia 10.3%, diarrhoea 35.9%, nausea 2.6%, vomiting 5.1%, lethargy 15.4% and skin rash 7.7%. For the pts treated at RDL, the objective tumour response rate was 11.1% (3 partial responses [PRs]; 95% confidence interval [CI]: 2.4–29.2%) and the disease control rate was 40.7% (3PRs, 8 stable diseases lasting for ≥12 weeks). The median time to progression was 4.2 months and median survival was 9.3 months. Six-month progression free survival was 22.2% (95% CI: 6.5–37.9%) and 6-month overall survival was 73.4% (95% CI: 56.5–90.3%). Preliminary pharmacokinetic data suggested that the addition of irinotecan to gefitinib resulted in an average of 14–33% increase in exposure to gefitinib (p<0.05). Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable. Gefitinib did not appear to add substantial efficacy to irinotecan. The relative low dose of irinotecan at the RDL and the rarity of EGFR somatic mutation in CRC may be contributory to the modest activity of irinotecan and gefitinib combination. [Table: see text]
Induction chemotherapy (ICT) followed by pre-operative chemoradiotherapy in locally advanced rectal cancer
Authors: Elkerm Y. , Elrewiny M. , Al-Batran S. , Jager E. , Elsaid A. 
Published: March 2020

13531 Background: Preoperative radiotherapy (RT)with or without chemotherapy (CRT) for patients (ptns) with T3,4 rectal carcinoma is increasingly accepted.We presented, 3 yrs ago, our experience with Cisplatin-5FU-Folonic(FA)regimen (FOLFC) in patns with metastatic CR carcinoma.We proved it is comparable to other regimens with lower cost. Methods: Between 10/99 & 8/04, 104 ptns between 18 and 65 year old (PS 0–1) were assessed retrospectively (24 T3 & 80 T4). Ptns received 2 months of ICT Cis(40mg/m2 D1)+FA(200mg/m2 2hrs infusion D1,2)followed by 5FU bolus(400 mg/m2 D1,2)+5FU cont inf(1200 mg/m2 D1–2)this cycle repeated q 2 wks for 8 wks. Starting on wk 9, 5 FU-FA was given as in Mayo-clinic regimen (D1–5, D21–25) with concomitant RT 45Gy in 25 fractions followed by 9 Gy boost to primary tumor. TME was planned at 4–6 wks from completion of ICT. 2 more cycles of FOLFC was given post-operatively. Results: All ptns (104) undergoing CRT completed therapy as planned, with no treatment-related interruptions. No GIII-IV toxicity. The radiological RR (after ICT) was 75% and (4 wks after CRT) was 89% (20CRs, 73PRs). 92% of ptns had subjective R in a median of 24 days from start of ICT in terms of improvement of diarrhea/constipation (90.4%), in obstructive symptoms (40/ 50 ptns)&weight gain in 100% of ptns.Reduced rectal bleeding (100%) & pelvic pain (100%). 17 of 20 ptns who were considered to be inoperable prior to the treatment underwent TME with negative radial margins. Anastomotic leakage occurred in 8 ptns (7.7%). Wound infection occurred in 4 ptns (3.8%). Delayed complications occurred in 3 ptns one required surgery for a stomal stricture. All ptns underwent R0 resection with clear CRM. Pathological CR was found in 32 ptns and in an additional 41 ptns, only microscopic tumor foci were found on surgical specimens. After a median follow-up of 16 months, two ptns had developed LR. Conclusions: ICT followed by synchronous CRT and TME results in marked tumor regression, rapid symptomatic response and achievement of R0 resection. The majority of ptns considered inoperable prior to receiving this treatment underwent successful excision. Given the low toxicity and promising activity, this regimen is being compared to standard synchronous 5FU- pelvic chemoradiation in a randomized study. No significant financial relationships to disclose.
Evaluating carcinoembryonic antigen (CEA) and tumor size as predictors of outcome in patients receiving capecitabine (X) plus oxaliplatin for metastatic colorectal cancer (MCRC): findings from a retrospective analysis
Authors: Jonsson F. , Twelves C. , Tabernero J. , Schoffski P. , Sobrero A. , Van Cutsem E. , Díaz-Rubio E. , Cassidy J. , Claret L. , Zuideveld K. 
Published: March 2020

13534 Background: The oral fluoropyrimidine X has superior efficacy and improved safety compared with bolus 5-FU/LV in CRC. Twice-daily oral X is replacing 5-FU as the backbone of combination regimens. The combination of X and 3-weekly oxaliplatin (XELOX regimen) has demonstrated similar efficacy to FOLFOX with some safety advantages and enhanced convenience in phase II/III clinical trials. The objective of this retrospective study was to investigate the use of CEA as an early predictor of outcome. Methods: The data used in this analysis came from a previously published large phase II study (n=96) of XELOX as first-line treatment for patients with MCRC [Cassidy et al. J Clin Oncol 2004]. A population-based pharmacodynamic analysis of CEA and tumor size progressions was performed. The resulting data were linked to hazard models for the secondary clinical endpoints: time to disease progression (TTP) and overall survival. As we were interested in early prediction, model-predicted time courses of CEA and tumor size (up to 10 weeks) were examined as covariates in the hazard models. The resulting predictions for TTP and survival based on either measure were tested and compared using stochastic simulations. Results: An indirect effect model provided the best description of CEA progression. For tumor size, a similar indirect effect model with an added resistance term gave the best description. CEA performed marginally better than tumor size in predicting survival and less well in predicting TTP. For survival the misclassification rate decreased from 0.426 to 0.404 when using tumor size and to 0.396 when using CEA as predictors. Conclusions: CEA and tumor size were found to have clinically equivalent power as early phase predictors of clinical outcome. [Table: see text]
Bevacizumab (BV) induced hypertension (HT): A manageable toxicity
Authors: Pande A. U. , Lombardo J. C. , Fakih M. , Wong M. K. , Iyer R. V. , Kuvshinoff B. W. , Javle M. M. 
Published: March 2020

13539 Background: BV inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). Anti-VEGF therapy blocks nitric oxide and causes relative vasoconstriction leading to HT in some patients (pts). Guidelines for anti-hypertensive (anti-HT) therapy in this setting are not well-established. Methods: Medical records of pts treated with BV from Oct. 2003 to Sep. 2005 were reviewed to document the incidence and treatment outcomes of BV induced HT. Grading of HT was as per CTC version 3.0. Institutional review board approval was obtained for this investigation. Results: One hundred fifty-four pts were treated with BV during study period. Fifty-five (35%) pts with colon (n=44), pancreatic (n=8), renal cell (n=2) and small cell lung cancer (n=1) had HT: 11 developed new-onset HT, 41 experienced exacerbation of pre-existing HT & 3 with prior HT became normotensive. BV was given with FOLFOX (n=38), FOLFIRI (n=5), gemcitabine & capecitabine (n=8) or interferon (n=4). Median dose of BV was 10 mg/kg (range=5–15 mg/kg). HT occurred after a median of 11 weeks after BV therapy (range=3–33 weeks). HT grading: grade 1 (n=1), grade 2 (n=29) & grade 3 (n=22). HT was controlled (BP≤140/90) in 44 (80%) and BP was >140/90 in 8 pts (BV was discontinued in 3). Complications of HT were chest tightness (n=1) and TIA (n=1). Anti-HT therapies are described in table 1 . Quinapril was commonly used (n=31): median dose of 20mg qd (range 5–40 mg). Renal function abnormalities occurred in 13 pts (creatinine 1.3–3.3), and proteinuria occurred in 7/27 pts. Conclusion: Exacerbation or new onset HT occurred in 35% of BV-treated pts after a median of 11 weeks. BV-induced HT is controllable in most cases with standard anti-HT therapy such as ACE-I. BV interruption and serious complications from HT are uncommon. [Table: see text] [Table: see text]
Phase-2 study of neoadjuvant chemoradiation in locally advanced rectal adenocarcinoma: The Radio-Xelox study
Authors: Salimichokami M. , Vafai M. , Derakhshani S. , Aminian S. , Vaheed A. A. 
Published: March 2020

13549 Background: Neoadjuvant Radiation treatment has been shown in many studies to decrease the incidence of loco-regional relapse in pts with locally-advanced Rectal Adenocarcinoma. Capecitabine and Oxaliplatin are both effective antineoplastic drugs in Colorectal Adenocarcinoma. They also have radiosensitizing effects. Hence,it is rational to combine these agents in association with radiotherapy,to achieve local controle and prevent systemic spread of the cancer. Methods: Thirty-eight pts with Rectal Adenocarcinoma (T3-T4 and/or N+) received radiation treatment (2.0 Gy, 5days a wk over 5 wks,total dose 50 Gy) plus oral Capecitabine at 600 mg/m2 twice a day and iv Oxaliplatin at 35 mg/m2 once weekly × 5wks. Surgery was performed 6wks post completion of XRT. Our end points were safety/feasibility and response/efficacy as demonstrable by the rate of pathologic complete remission (path-CR). Results: Seven pts (20%) acheived path-CR. Diarrhea was the most important severe adverse effect (in 25% of pts). fourteen pts (40%) showed good regression (very few cancer cells in fibronecrotic tissue Dworak grade 3). The remaining 17 pts showed less favorable regression or no significant change. Conclusions: Preoperative Radiation treatment plus chemotherapy with XELOX regimen is feasible, safe and effective with an impressive rate of path-CR in locoregionally advanced Rectal Adenocarcinoma. No significant financial relationships to disclose.
First-line bolus IFL and second-line FOLFOX: A retrospective review of two hundred thirty patients
Authors: Heng D. , Kennecke H. , Gill S. , Kollmannsberger C. , Lohrisch C. , Shah A. , Melosky B. 
Published: March 2020

13555 Introduction: The IFL regimen (irinotecan, 5-fluorouracil bolus and leucovorin) is active in metastatic colorectal cancer. Early treatment-related deaths in N9741 led to the utilization of a dose-reduced schema. An infusional regimen (FOLFIRI) replaced IFL because of superior tolerability. FOLFOX can be used as second-line therapy in patients treated previously with IFL. Methods: A retrospective review was performed at the British Columbia Cancer Agency to evaluate both the safety and outcome of all patients given IFL as first-line treatment for metastatic colorectal cancer. Data on second-line FOLFOX was also collected. Between March 31/2002 and April 1/2004, 230 patients were treated. Results: The mean number of IFL cycles delivered was 4.6 (18 doses) for a mean duration of 7.1 months. Toxicity was manageable with only 1 treatment-related death. 17% of patients had grade 3/4 toxicities that included neutropenia and diarrhea. Only 6% of patients required hospitalization during IFL treatment. The median survival of the entire group was 16.6 months (95% CI 14.3–18.6). One hundred twelve patients received second-line therapy. Forty-nine of these patients (44%) received infusional oxaliplatin (mFOLFOX 6) as second-line therapy. 27% had grade 3/4 toxicities and 10% required hospitalization. The median survival of these patients was 25.2 months (95% CI 20.1–30.3). Conclusion: This population-based study demonstrated that bolus IFL played a significant role in the treatment of metastatic colorectal cancer and had a manageable toxicity profile. Lastly, the sequence of IFL followed by FOLFOX resulted in a very meaningful patient survival of over 25 months. No significant financial relationships to disclose.