PubMed Health⌕ Search

Biomedical subjects

D J Wagener

Publications and source records attributed to D J Wagener.

At least 19 recordsLinked to original sources
PubMed2006

Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study.

BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.

Adenocarcinoma↗
PubMed2001

Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors.

R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881+/-393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.

Administration, Oral↗
PubMed2001

Phase II study of a combination of cyclophosphamide, adriamycin and cisplatin in advanced fallopian tube carcinoma. An EORTC gynecological cancer group study. European Organization for Research and Treatment of Cancer.

OBJECTIVE: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease. METHODS: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days. RESULTS: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively. CONCLUSION: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.

Adenocarcinoma↗
PubMed2000

Effect of carbogen breathing on the pharmacodynamics of 5-fluorouracil in a murine colon carcinoma.

To determine whether carbogen breathing has an effect on 5-fluorouracil (5-FU) uptake, retention and metabolism in C38 murine colon tumours grown in C57Bl/6 mice, we used in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. Eleven tumour-bearing mice were treated with 150 mg/kg of 5-FU given intraperitoneally (i.p.). Five mice received carbogen gas (95% O(2) and 5% CO(2)) for 9.5 min, starting 1 min before 5-FU administration. We found increased levels of 5-FU and its anabolites and catabolites by sequential ¿19F NMR spectroscopy in the group treated with 5-FU in combination with carbogen compared with the group treated with 5-FU alone. The maximum of normalised values of 5-FU and its metabolites, reached after carbogen breathing, was almost 2-fold higher than after treatment with 5-FU alone. Despite these increased concentrations no significant effect of carbogen on growth inhibition of the tumour by 5-FU was observed, which may be related to the size as well as the well vascularised and perfused conditions of the tumours studied.

Administration, Inhalation↗
PubMed1999

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule.

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min i.v. infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 microg m(-2). According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 microg m(-2), the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 microg m(-2). From the dose level 170 microg m(-2), the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 microg m(-2). The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml(-1)) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values.

Adult↗
PubMed1999

Phase I and pharmacologic study of oral (PEG-1000) 9-aminocamptothecin in adult patients with solid tumors.

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m(2)/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m(2)/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r(2) = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m(2)/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

Administration, Oral↗
PubMed1998

A clinical pharmacokinetics study of carzelesin given by short-term intravenous infusion in a phase I study.

We investigated the pharmacokinetic behavior of carzelesin in 31 patients receiving this drug by 10-min intravenous infusion in a Phase I clinical trial, which was conducted at institutions in Nijmegen (institution 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 microg/m2. Carzelesin is a cyclopropylpyrroloindole prodrug that requires metabolic activation via U-76,073 to U-76,074. The lower limit of quantitation (LLQ) of the high-performance liquid chromatography (HPLC) method used in this study was 1 ng/ml for the parent drug and its metabolic products. Carzelesin was rapidly eliminated from plasma (elimination half-life 23 +/- 9 min; mean value +/- SD). At all dose levels, U-76,073 was found as early as in the first samples taken after the start of the infusion. However, the concentration of U-76,074 exceeded the LLQ for only short periods and only at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC50 values obtained by in vitro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance observed between patients from institution 1 (7.9 +/- 2.1 l h[-1] m[-2]) and those from institution 2 (18.4 +/- 13.6 l h[-1] m[-2]; P = 0.038), probably reflecting problems with drug administration in the latter institution. The results recorded for patients in institution 1 indicated that the AUC increased proportionately with increasing doses. There was a good correlation between the maximal plasma concentration and the AUC, enabling future monitoring of drug exposure from one timed blood sample. Urinary excretion of carzelesin was below 1% of the delivered dose.

Antineoplastic Agents↗
PubMed1998

Quantitative ultrasonic analysis of liver metastases.

The performance of five features of ultrasonic tissue characterization (UTC) of metastases in vivo in liver was investigated. We acquired serial radiofrequency data sets of 12 patients with metastases in the liver from adenocarcinoma of the colon. Parenchyma and metastases UTC features were estimated in semiautomatically segmented regions. Over 200 metastases were measured in patients and 43 dummy metastases in healthy volunteers. Two attenuation features could be estimated in only 15% of the metastases, and these were not different from those in parenchyma. The texture features signal-to-noise ratio (SNR) could not discriminate real from dummy metastases. Average backscatter intensity, b0, is an established discriminative echographic image feature. However, the metastases that were hypoechoic relative to surrounding parenchyma appeared to be isoechoic relative to normal liver parenchyma. They were visible because of an increased b0 in the surrounding liver parenchyma. Finally, we found an increased backscatter coefficient slope vs. frequency in hypoechoic metastases that may predict a deterioration of lesion contrast at higher transducer frequencies. We conclude that the backscatter coefficient slope can improve detection of metastases, and that b0 measured relative to normal liver parenchyma should be used to correctly correlate metastasis echography with histology.

Acoustics↗
PubMed1998

Significance of cell proliferation measurement in gastric cancer.

Cell kinetic data may be important indicators of clinical behaviour in many types of cancer. Recently, several antibodies to cell-cycle associated antigens have been characterised. This overview summarises the advantages and disadvantages of different methods for the assessment of cell proliferation. Moreover, the prognostic value of proliferative activity in gastric cancer is discussed and suggestions for future research are given.

Antigens, Nuclear↗
PubMed1998

The ESMO programme of certification and training for medical oncology.

ESMO has designed a programme of certification and training in medical oncology. In this paper the background of these programmes is given, and the programme of graduate education is described in greater detail. The standard requirements are a total training period of six years, beginning with a common internship in internal medicine of at least two years, followed by a training programme in oncology for three to four years, which must include at least one year of full-time clinical training in the diagnosis and management of neoplastic diseases, accompanied by one year of experience in an ambulatory care setting.

Certification↗
PubMed1998

5-Fluorouracil in colorectal cancer: rationale and clinical results of frequently used schedules.

Colorectal cancer is one of the most frequent cancers in the western world. Approximately half of the patients will die of their disease because of metastases. The most active cytotoxic agent used to date is 5-fluorouracil (5-FU). However, clinical responses are achieved only in a minority of patients. Based on the current knowledge of the mechanism of action of 5-FU, many attempts have been made to improve the clinical results. These include the use of biochemical modulators and different methods of administration, and these are the subject of this review. Specifically, of five different modulators, i.e. leucovorin, methotrexate, interferon-alpha, N-(phosphonacetyl)-L-aspartate and trimetrexate glucuronate, the biochemical background and the clinical results obtained with these modulators are discussed. In order to get more insight, an overview of the 5-FU metabolism has been given. In addition, the different methods of systemic administration of 5-FU as well as possible mechanisms underlying 5-FU resistance are described.

Antimetabolites, Antineoplastic↗
PubMed1998

Enhanced myelotoxicity due to granulocyte colony-stimulating factor administration until 48 hours before the next chemotherapy course in patients with small-cell lung carcinoma.

PURPOSE: To evaluate the impact of granulocyte colony-stimulating factor (G-CSF) priming on peripheral-blood cell counts during standard-dose chemotherapy. PATIENTS AND METHODS: Twelve patients with relapsed small-cell lung carcinoma (SCLC) were treated with two chemotherapy courses. Six patients received G-CSF priming only before the first course (group A) and the other six patients only before the second course (group B). Each patient served as his own control. Patients were treated with cyclophosphamide, epirubicin, and etoposide (CEE), or with vincristine, ifosfamide, mesna, and carboplatin (VIMP) every 4 weeks. G-CSF was administered subcutaneously 5 microg/kg/d for 6 days until 48 hours before the first or second chemotherapy course. RESULTS: Priming caused a lowering of the WBC nadir, with a median value of 0.95 x 10(9)/L (P = .004), and of absolute neutrophil nadir, with a median value of 0.48 x 10(9)/L (P = .03). There was a trend for a lower platelet (PLT) nadir after G-CSF priming (P = .09). G-CSF priming resulted in a prolonged duration of WBC count less than 3.0 x 10(9)/L of +4.25 days (P = .04), and of WBC count less than 1.0 x 10(9)/L of +0.50 days (P = .03). The duration of neutropenia less than 0.5 x 10(9)/L seemed longer in primed courses (+3.75 days, P = .18). The duration of PLT counts less than 100 x 10(9)/L was prolonged by 1.5 days (P = .04). Hemoglobin (Hgb) levels were not influenced by G-CSF priming. CONCLUSION: G-CSF administration until 48 hours before the next chemotherapy course increases chemotherapy-associated leukocytopenia and thrombocytopenia. This may be of special concern when G-CSF is administered during dose-densified chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Weekly chronomodulated 48 h infusion of high-dose 5-fluorouracil modulated by methotrexate and (6S)-leucovorin in advanced colorectal cancer: a phase IB study.

In this phase IB study, 24 patients with advanced colorectal cancer were treated with escalating doses of weekly chronomodulated 48 h infusions of 5-fluorouracil (5-FU) biochemically modulated by methotrexate 40 mg/m2 and (6S)-leucovorin 8 x 45 mg orally. Two daily peak delivery periods (PDP), during which 65% of the daily dose was administered, were investigated: from 18.00 to 0.30 h and from 0.00 to 06.30 h. The maximal tolerated dose of 5-FU was 2800 mg/m2/48 h, with a PDP from 18.00 to 0.30 h.

Adenocarcinoma↗
PubMed1997

Dose intensification of chemotherapy and the role of granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor in small cell lung cancer.

The natural history of small cell lung cancer (SCLC) is characterized by early dissemination. Despite the high responsiveness to chemotherapy, the disease remains ultimately fatal in the majority of patients. One of the strategies to improve final outcome is the administration of intensified chemotherapy, either by dose escalation or by chemotherapy given at shortened intervals. By now, in only one randomized study, in which cyclophosphamide and cisplatin dosage was escalated by 30% in the first course only, a survival advantage was demonstrated in limited disease patients. The different ways of achieving intensification of chemotherapy are highlighted. The addition of growth factors in current dose-escalated or accelerated schedules seems to result in a relative dose intensity of no more than 150% when compared to optimally delivered conventional regimens. Whether such a moderate degree of dose intensification will improve survival rates has to be awaited from phase III trials.

Antineoplastic Agents↗
PubMed1996

5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by 19F NMR spectroscopy.

High-resolution 19F NMR spectroscopy at 9.4 T was used to study the difference in the metabolite pattern of 5-fluorouracil (5-FU) between viable and necrotic tissues of C38 murine colon tumors grown in C57BI/6 mice. Studies were performed on perchloric acid extracts of these tumor fractions after 5-FU treatment. The 19F nuclear magnetic resonance spectra exhibited resonances representing 5-FU, the catabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine, as well as several fluoronucleotide anabolites. The absolute concentrations of anabolites and catabolites and the anabolite-to-catabolite ratio were significantly lower in the necrotic fraction than in the viable tumor fraction 50 min after administration of 5-FU, whereas the absolute concentration of 5-FU was the same. Therefore, in 5-FU metabolism studies with NMR spectroscopy, it is important to consider the necrotic contribution to the tumor volume.

Animals↗
PubMed1996

Results of a phase II trial of epirubicin and cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: an EORTC GITCCG study.

The objective of the present study was to define the role of chemotherapy, in the form of the EP regimen, consisting of epirubicin (E) and cisplatin (P) in addition to irradiation in combination with 5-fluorouracil (5-FU) for treatment of pancreatic cancer. 53 eligible patients with histologically or cytologically proven locally advanced pancreatic cancer were treated with three cycles of E 60 mg/m2 (if this dose was well tolerated then the dose of E was increased by 10 mg/m2 in the next cycle; 80 mg/m2 was the maximum dose for the following cycles) and P 100 mg/m2 once every 3 weeks, followed after 4 weeks by a split course of irradiation of 40 Gy with 5-FU 500 mg/m2 on each of the first 3 days of each 20 Gy treatment segment. This was followed by another three cycles of EP in patients who achieved stable disease (SD) or a better response after the first three cycles. The treatment given with standard anti-emetics was moderately tolerated. The chemotherapy related toxicity consisted mainly of myelosuppression and the chemoradiotherapy related toxicity of gastrointestinal side-effects. However, due to the long duration of treatment which made the whole treatment difficult to endure, only 18/53 (34%) actually completed the full treatment regimen. Responses were evaluated after the first three cycles and 4 weeks after the completion of the treatment by serial CT-scans using standard criteria. The results in 53 evaluable patients after the first three cycles of EP were as follows: 1 patient achieved a clinical complete response (CR), 7 a partial response (PR) (CR + PR: 15%; 95% confidence interval (CI): 11-33%), 36 patients (68%) had stable disease (SD) and 6 patients progressive disease (PD). There was 1 early PD, 1 toxic death and 1 patient could not be evaluated. The response at the end of the treatment was 3 CR, 11 PR (CR + PR: 14/53 (26%); 95% CI: 15-40%), 30 SD and 6 PD. The median time to progression was 8.9 months and the median duration of response 13.1 months. The median survival of all treated patients was 10.8 months (range 7 days to 41.5 months), of responders 15.1 months and, of the patients with SD 10.3 months. These results are comparable to other combined modality regimens reported in the literature for locally advanced disease. The addition of the systemic treatment with E and P offers no additional advantage to combined modality treatment alone.

Adenocarcinoma↗
PubMed1996

Multicentre phase II pharmacological evaluation of rhizoxin. Eortc early clinical studies (ECSG)/pharmacology and molecular mechanisms (PAMM) groups.

Rhizoxin is a macrocyclic lactone compound that binds to tubulin and inhibits microtubule assembly. Rhizoxin demonstrated preclinical anti-tumour activity against a variety of human tumour cell lines and xenograft models. Phase I evaluation found a maximum tolerated rhizoxin dose of 2.6 mg m-2, with reversible, but dose-limiting, mucositis, leucopenia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in melanoma, breast, head and neck, and non-small-cell lung cancers with the recommended phase II rhizoxin dose of 2 mg m-2. Pharmacological studies were instituted with the phase II trials to complement the limited pharmacokinetic data available from the phase I trial. Blood samples were obtained from 69 of 103 eligible patients enrolled in phase II rhizoxin studies, and these were evaluable for pharmacokinetic analysis in 36 patients. Plasma rhizoxin concentrations were determined by high-performance liquid chromatography (HPLC), and post-distribution pharmacokinetic parameters were estimated by a one-compartment model. Rhizoxin was rapidly eliminated from plasma, with a median systemic clearance of 8.41 min-1 m-2 and an elimination half-life of 10.4 min. Rhizoxin area under the concentration-time curve (AUC) was higher in patients obtaining a partial response or stable disease than in those with progressive disease (median 314 vs 222 ng ml-1 min; P = 0.03). As predicted from previous studies, haematological and gastrointestinal toxicity was observed, but could not be shown to be related to rhizoxin AUC. This study demonstrated the rapid and variable elimination of rhizoxin from the systemic circulation. The presence of pharmacodynamic relationships and the low level of systemic toxicity suggest that future trials of rhizoxin with alternative dosage or treatment schedules are warranted.

Antibiotics, Antineoplastic↗