Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.
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PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. 1280 93

Emergency operations for obstructing colorectal cancer are associated with high morbidity and mortality rates and often result in a temporary or permanent colostomy. A colorectal stent can be used both for palliation and as a "bridge to surgery". Twenty-three patients with obstructive sigmoid or rectal cancer were selected for stenting. Self-expanding metal mesh stents were placed under endoscopic and flouroscopic guidance. Stent placement was technically successful in 19 patients and clinical success was seen in 18. There were only three minor complications, no major and no procedure related mortality. Four patients were later resected without a diverting stoma, two with rectal cancer had preoperative MRI and radiotherapy. In 15 patients the procedure was regarded as palliative. Stent migration was noted in four patients but symptomatic reobstruction did not occur, no patient needed later surgery. Colorectal stenting procedure is effective and safe and can be used in obstructing cancers both as a temporary relief before elective resection and as a definitive treatment in palliative cases.
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PMID:[Self-expanding stent in obstructing colorectal cancer. A new technique to avoid abdominal surgery]. 1283 30

Colon and rectal cancer are in France a challenging problem in public health, reaching the second place in cancer related deaths. Surgery is still the key of curative treatment. Crude survival increased from 33% to 55% during twenty years. Colonoscopy is the referent exam for positive diagnosis. In rectal cancer, endorectal ultrasound and MRI have optimised local staging. The quality of general staging is important since it could change therapeutic strategy. Spiral CT scan is now probably superior to conventional ultrasound in the detection of liver metastases. Laparotomy is still the standard surgical approach. Main prospective studies in the evaluation of laparoscopic approach are still ongoing. Rectal resection for cancer is today a standardised procedure: total mesorectal excision (TME) should be done for rectal tumours below peritoneal reflection; TME decreases both the risk of local recurrence and the frequency of urogenital sequelae. The quality of surgical resection for colorectal cancer should always be checked and particularly, the number of lymph nodes, the longitudinal and lateral margins for rectal cancer, and resection for fixed tumours. Adjuvant chemotherapy with 5 fluorouracil and folinic acid is a standard for UICC stage III patients, but with a clearer benefit for colon tumours. Preoperative irradiation for T3-T4 rectal tumours is an European standard, providing a better local control; irradiation could also improved survival. In the oncoming years, surgeon and hospital specialization will probably be the main factor of progress in the management of colorectal cancer in France.
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PMID:[Colorectal cancer: what should be the management of primary tumour?]. 1508 58

The relations of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters to microvessel density (MVD), histologic grade, and presence of metastasis were evaluated to establish new prognostic indicators in colorectal cancer (CRC). Fast-low angle shot DCE-MRI parameters (time-intensity curves, TICs; maximal relative enhancement within the first minute, E(max/1); maximal relative enhancement of the entire study, Emax; steepest slope of the contrast enhancement curve; and time to peak enhancement) of 21 CRCs (seven Duke stage B, 12 Duke stage C, and two Duke stage D) were retrospectively evaluated and correlated with corresponding postoperative MVD measurements, histologic grades, and presence of metastasis at 2 years. TICs were classified as type A in nine (43%), type B in seven (33%), and type C in five cases (24%). There was a significant difference between TIC types with regard to MVD (p < 0.05-0.001). Time to peak enhancement, steepest slope of TIC, and E(max/1) were strongly correlated with MVD (r = -0.765, p < 0.01; r = 0.681, p < 0.01; r = 0.634, p < 0.01; respectively). MVD, steepest slope of the enhancement curve, E(max/1), and Emax strongly correlated with histologic grade (r = 0.475, p < 0.05; r = 0.683, p < 0.01; r = 0.687, p < 0.01; r = 0.791, p < 0.01; respectively). There was a significant difference between groups of patients with and without metastasis with regard to histologic grade (p < 0.05) and two of the DCE-MRI parameters (p < 0.005 for E(max/1) and p < 0.05 for time to peak enhancement). Discriminant analysis correctly predicted the metastatic occurrence at 2 years in 90.5% of cases using E(max/1) (p < 0.001). Histologic grade resulted in lower rates of discrimination (66.7%; p < 0.05). DCE-MRI parameters may help in the prediction of MVD and histologic grade in CRC and may be used to predict therapeutic outcome.
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PMID:Dynamic MRI in indirect estimation of microvessel density, histologic grade, and prognosis in colorectal adenocarcinomas. 1529 Sep 41

This article reviews published data regarding CT colonography and discusses both technical and medical aspects of its development over the last 10 years. Although colonography can be performed using MRI instead of CT, mainly CT aspects are dealt with. The technical development of CT to the current generation of Multi-detector-row-CT is explained, and the influence of various factors (slice thickness, dose, patient preparation, post processing) is discussed. The method has a high sensitivity and specificity as well as a high negative predictive value for the detection of polyps > or = 1 cm, but is currently still insufficient in the detection of polyps < 5 mm. It is a valid alternative after incomplete optical colonoscopy and an alternative in patients with "high-risk" for conventional endoscopy. In the future it may become an alternative for conventional endoscopy in screening programs for colorectal cancer.
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PMID:[CT colonography --"virtual colonoscopy"--a current review]. 1550 62

It is acceptable that the stage of disease at time of attendance of patients with colorectal cancer (CRC) is the defining factor for patients' survival rate. From 1986 until 1998, 417 patients were treated in the Department of Surgery of the General Hospital of Edessa with CRC. For diagnosis, established endoscopic procedures were followed. CT, USG, MRI and histology were performed for staging. 85.4% of the patients had stage II, III and IV TNM/UICC tumour at the time of attendance.
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PMID:Stage of disease at time of attendance of patients with colorectal cancer at the Department of Surgery of the General Hospital of Edessa. 1565 21

Many novel antiangiogenic agents are currently in various phases of clinical testing. These agents tend to be cytostatic, and therefore few responses are observed with conventional imaging by computerized tomography. Furthermore, toxicity with these agents is seen when the maximum-tolerated dose is combined with chemotherapy. Hence, there is a need to develop imaging strategies that can determine the minimum and optimum biologically active doses. There is increasing awareness of the need to obtain evidence of drug activity through the use of surrogate markers of the biologic mechanism of action during early clinical trials, in addition to determining the pharmacokinetics, toxicity profile, and maximum-tolerated dose. One of the major impediments to the rapid development of antiangiogenic agents in the past has been the lack of validated assays capable of measuring an antiangiogenic effect directly in patients. Recently, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has emerged as a useful technique for noninvasive imaging of tumor vasculature in preclinical and clinical models. The problem of tumor heterogeneity remains to be addressed. The major challenge is the standardization of the technique worldwide for the purpose of early clinical studies that are likely to be multicenter. Convincing data on correlations between changes observed through molecular imaging and changes in tumor angiogenesis, and hence tumor biology, are still lacking. Whether this would translate into a survival advantage remains to be seen. The ultimate test of the surrogate biological end points determined by molecular imaging will occur in randomized phase III trials. Results of the first randomized trial that showed a survival advantage in favor of antiangiogenic agents were released at the American Society of Clinical Oncology meeting in 2003. There it was reported that the combination of 5-fluorouracil, leucovorin, and irinotecan (Camptosar; Pfizer Pharmaceuticals; New York, NY) with anti-vascular endothelial growth factor antibody (bevacizumab-Avastin; Genentech, Inc.; South San Francisco, CA) was superior to the chemotherapy regimen alone when used to treat patients with metastatic colorectal cancer. However, until further phase III clinical trials confirm these results, surrogate end points of clinical efficacy of the newer agents are urgently needed so that development of ineffective drugs can be halted early. This review briefly discusses the role of molecular imaging in general, and DCE-MRI in particular, in relation to treatment with antiangiogenic agents and highlights some of the difficulties encountered in this area.
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PMID:Molecular imaging of antiangiogenic agents. 1570 11

Adenocarcinoma of the colon and rectum is currently diagnosed in about 783,000 new cases annually and 437,000 patients will die of the disease each year worldwide. Colorectal cancer presents as an emergency situation (obstruction, bleeding or perforation) in approximately 25% of cases and with more or less obvious chronic symptoms in the rest of cases. Rectal cancer patients, with a T1 tumour can be offered local excision whereas patients with more advanced cancer must be offered a more radical abdominal procedure. In large bulky tumours (T3 or definitely T4), MRI should guide the choice of preoperative radiotherapy. Three major indications for radiotherapy are reduction of local recurrences in mobile rectal cancer in order to improve survival, down-staging of the tumour in primary irresectable tumours, and downsizing of low-lying tumours in an attempt to perform a sphincter-saving procedure. The surgical strategy is to remove the tumour-bearing bowel segment with, if possible, a locoregional curative procedure, to restorate bowel continuity, and to ensure an optimal quality of life. In most situations, it is possible to achieve local radical resection. In rectal cancer surgery, the main problem is to stick to the embryological planes during the whole procedure. The whole mesorectum is taken out as a packet down to the level of division. This TME procedure dramatically reduced the local recurrence rate to 3%-7%. Surgeon case volume may be an important factor in cancer surgery success. Laparoscopic surgery for colorectal cancer has stimulated a great deal of interest in recent years, but there are concerns regarding this type of surgery. In conclusion, modern surgery for colorectal cancer is a well-defined technique where the anatomical planes have to be identified. Care must be taken to learn all the essential steps. Data from the literature strongly support that the surgeon is the most important factor for an excellent outcome.
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PMID:Good colorectal cancer surgery. 1586 91

To determine the correlation between serum CEA level and the metabolic volume by FDG PET in postoperative patients with recurrent colorectal cancer, FDG PET was performed in 29 consecutive patients with recurrent or metastatic colorectal cancer whose CEA levels were higher than 5 ng/ml. A whole body emission scan was performed 60 minutes after injecting 370-555 MBq of F-18 FDG. "PET volume" and "PET metabolic volume" of tumors were measured on FDG PET images. Based on an isocontour plot of tumor mass at 2.5 SUV (standardized uptake value), the metabolically active tumor "PET volume" was calculated. "PET metabolic volume" was obtained by multiplying the "PET volume" by the mean SUV of the tumor. All recurrent or metastatic lesions were single or multiple lesions of measurable size (axial diameter > 1 cm, minimum "PET volume" 3.5 cm3), and were verified by operation or by other imaging modalities (CT or MRI). There was a linear associations between "PET volume" and serum CEA level. Further regression analysis by least squares showed a highly significant model with an equation of volume = 41.2 + 0.471 x CEA (r2 = 0.629). However, no such association was found between "PET metabolic volume" and serum CEA level according to the residual normality test. In conclusion, "PET volume" measured by FDG PET and serum CEA level in colorectal cancer are significantly correlated. Tumor volume determined by FDG PET can be used as an effective marker of tumor burden in postoperative patients with colorectal carcinoma.
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PMID:Correlation between serum CEA level and metabolic volume as determined by FDG PET in postoperative patients with recurrent colorectal cancer. 1590 92

PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. To assess the predictive value of a mouse model of tumor metastases, comparisons were performed for the biological activity of PTK/ZK in the mouse model and in patients with liver metastases in the clinical phase I trials. An orthotopic, syngeneic mouse model was used: C57BL/6 mice injected in the ear with murine B16/BL6 melanoma cells which metastases to the cervical lymph-nodes. The primary tumor and spontaneous metastases express VEGF and VEGF receptors and respond to treatment with VEGFR tyrosine kinase inhibitors. PTK/ZK was administered orally, with assessments by DCE-MRI of the metastases and plasma VEGF taken predose and at 3 days posttreatment and efficacy determined at 7 days posttreatment. Dose-ranging studies in naive mice provided preclinical pharmacokinetic data, while two dose-escalation phase I studies provided clinical pharmacokinetic data. An exposure-response relationship was observed both for mouse metastases (measured as % tumor weight treated/control) and for human liver metastases (measured as % regression). In the B16/BL6 model, the active dose of 50 mg/kg PTK/ZK yielded 62.4 (+/- 16.0) h microM plasma exposure, which is comparable to the plasma area under the concentration time curve (AUC) achieved by the 1000 mg dose of PTK/ZK used in clinical trials. At this exposure level in clinical trials, DCE-MRI showed a reduction in the area under the enhancement curve (IAUC) to 47% of baseline. At a similar exposure in the PTK/ZK-treated mice, a reduction in IAUC to 75% of baseline was observed. Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.
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PMID:Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. 1617 7


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