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Contains fulltext : 69307.pdf (publisher's version ) (Closed access), Imaging using ultrasonography, spiral CT, MRI and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), plays a major role at two situations during the management of patients with colorectal liver metastases: (a) at the time of the diagnosis and treatment of the primary colorectal tumour, and (b) during the follow-up for the detection of liver metastases and assessing the resectability of these metastases. At the time of the diagnosis and the treatment of the primary tumour, imaging comprising spiral CT or MRI to detect and characterize liver lesions is considered to be the modality of choice. Due to their low prevalence, imaging for the evaluation of lung metastases may be limited to conventional chest radiography. For evaluation of the extrahepatic abnormalities, abdominal and chest CT may be performed in combination with CT of the liver; alternatively a FDG-PET may be performed. During the follow-up of patients treated for colorectal carcinoma, ultrasonography is the most important imaging modality. However, if the liver cannot be adequately imaged by ultrasonography, if there is a raised level ofcarcinoembryonic antigen or irresectability cannot be determined, additional CT or MRI examination will result in more information. more...

Background: BN80915 (diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (d×5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity. Patients and methods: Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of diflomotecan and its metabolite BN80942 were quantified. Results: Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m2/day. The 0.15-mg/m2dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m2/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation. Conclusions: The MTD and RD of diflomotecan administered according to a d×5 repeated three weekly are 0.15 and 0.125 mg/m2/ day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan. more...

Contains fulltext : 148839.pdf (publisher's version ) (Open Access), PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with oral ZD9331 given once daily (od) or twice daily (bid) for 5, 7, or 10 days; cycles were repeated every 21 days at doses ranging from 2.5 to 40 mg. For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated liquid chromatographic-tandem mass spectrometry assay. Plasma levels of 2'-deoxyuridine were measured as a surrogate marker for TS inhibition. RESULTS: Forty-two patients received a total of 166 courses. The DLTs were myelosuppression and skin rash. Dose escalation of oral ZD9331 from 2.5 to 40 mg, as a single daily dose, resulted in a less than proportional increase in the plasma area under the concentration-time curve of ZD9331. The plasma drug exposure per cycle for the schedules 20 mg od for 5 days, 10 mg od for 10 days, and 10 mg bid for 5 days, all resulting in a total dose per cycle of 100 mg, were comparable. One partial response was noted in a patient with gastric cancer. CONCLUSION: DLTs in this phase I study of oral ZD9331 were myelosuppression and skin toxicity. The recommended dose for phase II studies of oral ZD9331 is 20 mg od for 5 consecutive days, every 3 weeks. more...

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Contains fulltext : 22829___.PDF (publisher's version ) (Open Access)