A cost comparison of oral tegafur plus uracil/folinic acid and parenteral fluorouracil for colorectal cancer in Canada.

Background: Two randomised, controlled trials (n = 1396) comparing (i) intravenous fluorouracil (FU) plus oral folinic acid (leucovorin) and (ii) oral tegafur plus uracil (UFT) plus folinic acid for the treatment of metastatic colorectal carcinoma found both regimens to have equivalent efficacy in terms of survival, tumour response and time to disease progression. The UFT/folinic acid regimen was associated with a better toxicity profile than FU/folinic acid.

Objective: To determine the comparative frequencies and costs of healthcare resources utilised in the treatment of patients with these two regimens from a hospital and government perspective.

Two basic amino acids C-terminal of the proximal box specify functional binding of the vitamin D receptor to its rat osteocalcin deoxyribonucleic acid-responsive element.

Nuclear hormone receptor-responsive element binding specificity has been reported to reside predominantly in the proximal box (P-box), three amino acids located in a DNA-recognition alpha-helix situated on the C-terminal side of the first zinc finger. To further define the residues in the vitamin D receptor (VDR) DNA binding domain (DBD) that mediate its interaction as a retinoid X receptor (RXR) heterodimer with the rat osteocalcin vitamin D-responsive element (VDRE), chimeric receptors were created in which the core DBD of VDR was replaced with that of the homodimerizing glucocorticoid receptor (GR). Systematic alteration of GR DBD amino acids in these chimeras to VDR DBD residues identified arg-49 and lys-53, just C-terminal of the P-box within the base recognition alpha-helix of human VDR (hVDR), as the only two amino acids among 36 differences required to convert the GR core zinc finger domain to that of the VDR.

Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours.

This phase I study was conducted to determine the recommended phase II doses, safety profile, and antitumour activity of a combination regimen of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours. Cisplatin and epirubicin were given at fixed doses of 50 and 60 mg m(-2), respectively. The irinotecan dose was escalated at 10 mg m(-2) increments from a starting dose level of 70 mg m(-2).

Antimicrobial susceptibility of Campylobacter spp. isolated from broiler chickens in Northern Ireland.

Between February 2000 and October 2001, cloacal swabs were collected from 387 broiler chicken flocks in Northern Ireland. Campylobacter isolates from the 262 positive flocks were tested with common antimicrobial agents using a disc diffusion method and by Etests. Resistance to erythromycin, gentamicin and chloramphenicol was <1%, whereas for ampicillin, nalidixic acid and tetracycline, resistance was 33%, 10% and 13%, respectively.

Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial.

Purpose: In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL).

Patients And Methods: Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients.

Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116).

Objective: ISIS 5132 is a 20-base phosphorothioate DNA oligonucleotide against human c-raf kinase, a downstream effector of ras oncogene function. C-raf kinase is a molecule in the MAP kinase signaling cascade which is essential for cellular proliferation, the overexpression of which leads to malignant expression. Activity of this compound was documented in a woman with ovarian cancer in a Phase I study.

The statins as anticancer agents.

3-Hydroxy-3-methylgutaryl CoA reductase inhibitors, commonly referred to as the statins, have proven therapeutic and preventative effects in cardiovascular diseases. Recently, there are emerging interests in their use as anticancer agents based on preclinical evidence of their antiproliferative, proapoptotic, anti-invasive, and radiosensitizing properties. Inhibition of 3-hydroxy-3-methylgutaryl CoA reductase by the statins interferes with the rate-limiting step of the mevalonate pathway, leading to reduced levels of mevalonate and its downstream products, many of which play important roles in critical cellular functions such as membrane integrity, cell signaling, protein synthesis, and cell cycle progression.

Sucralfate mouthwash for prevention and treatment of 5-fluorouracil-induced mucositis: a randomized, placebo-controlled trial.

A randomized, double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of a sucralfate mouthwash in preventing and alleviating oral mucositis induced by 5-fluorouracil (5FU). A total of 81 patients with colorectal cancer were enrolled. Patients were studied during their first cycle of chemotherapy with 5FU and leucovorin (LV) daily for 5 days every 4 weeks (Mayo Clinic schedule).

Assessment of tumor cell repopulation after chemotherapy for advanced ovarian cancer: pilot study.

Background: Repopulation of clonogenic tumor cells appears to increase during fractionated radiation treatment and is recognized as an important factor affecting local control. Given the longer intervals between cycles and longer total duration of treatment, the impact of repopulation is likely to be greater after chemotherapy.

Methods: We assessed tumor cell repopulation with the proliferative marker Ki-67 in 21 patients with ovarian carcinoma who received initial chemotherapy.

A phase I study of 99mTc-hR3 (DiaCIM), a humanized immunoconjugate directed towards the epidermal growth factor receptor.

A phase I trial was conducted to evaluate the safety, tumour and normal tissue localization, pharmacokinetics and radiation dosimetry of Tc-hR3, a humanized monoclonal antibody directed towards the epidermal growth factor receptor, in 12 patients with recurrent or metastatic epithelial malignancies. Patients were injected intravenously with 3.0 mg or 6.

The palliative benefit of irinotecan in 5-fluorouracil-refractory colorectal cancer: its prospective evaluation by a Multicenter Canadian Trial.

Most patients with colorectal cancer (CRC) who have failed initial 5-fluorouracil (5-FU) chemotherapy have worsening of disease-related symptoms (DRS) and quality of life (QOL). Irinotecan has a reported response rate of 10%-20% in such patients. The aim of this phase II trial was to prospectively determine the palliative benefit of irinotecan utilizing DRS as primary endpoints of response.

Donor CMV serostatus has no impact on CMV viremia or disease when prophylactic granulocyte transfusions are given following allogeneic peripheral blood stem cell transplantation.

We studied the impact of donor cytomegalovirus (CMV) serologic status on CMV viremia and disease when prophylactic granulocyte colony-stimulating factor (G-CSF)-mobilized granulocyte transfusions (GTs) were given following allogeneic peripheral blood stem cell (AlloPBSC) transplantation. A cohort of 83 patients who received 2 prophylactic GTs from ABO-compatible stem cell donors following AlloPBSC transplantation was compared with a cohort of 142 patients who did not. AlloPBSC donors were eligible for granulocyte donation irrespective of their CMV serostatus.

Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer.

Purpose: This phase III study compared the time to progression (TTP) of an oral regimen of dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine composed of a fixed combination of tegafur and uracil in a 1:4 molar ratio (UFT) and leucovorin (LV) to intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma (CRC) patients. Secondary end points were survival, tumor response, safety, and quality of life.

Patients And Methods: Between May 1996 and July 1997, 380 patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (90 mg/d), administered for 28 days every 35 days, or 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/d), given IV for 5 days every 35 days.

Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study.

Background: Because treatment of metastatic colon cancer is noncurative, new treatments are needed. This trial evaluated the antitumor effects of two targeted anticancer agents: (a) ISIS 3521, an antisense inhibitor of the protein kinase C alpha; and (b) ISIS 5132, an antisense inhibitor of c-raf kinase in patients untreated previously with recurrent or metastatic colorectal carcinoma.

Patients And Methods: All patients had colorectal adenocarcinoma with measurable disease and no prior chemotherapy for metastatic disease.

Clinical development of P glycoprotein modulators in oncology.

The last two decades have witnessed dramatic advances into the mechanisms of drug resistance in cancer. The identification of P glycoprotein (Pgp) as a specific mechanism led to the initial hope and expectation that it would be possible to modulate this and increase sensitivity to drug therapy. Clinical trials using first- and second-generation Pgp modulators did establish proof of principle that in some settings, clinical drug resistance could be overcome with the addition of a Pgp modulator-for example, clinical resistance to paclitaxel, a Pgp substrate, in women with ovarian cancer was shown to be overcome in approximately 20% with the addition of PSC 833, a highly effective Pgp modulator.

Detection of heat-stable antigens of Campylobacter jejuni and C. coli by direct agglutination and passive hemagglutination.

The two serotyping schemes for the detection of heat-stable antigens of Campylobacter jejuni and Campylobacter coli use the same strains for antiserum production but differ in the detection systems used for identifying agglutination. The Penner method uses passive hemagglutination (PHA) while the Laboratory of Enteric Pathogens method uses the same antisera but in a whole-bacterial-cell direct agglutination (DA) protocol. C.

A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer.

A multicentre, randomised study was carried out in Europe, South Africa and North America to compare the activity and tolerability of oral versus intravenous (i.v.) topotecan in patients with relapsed epithelial ovarian cancer.

Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene.

The functional significance of two unlinked human vitamin D receptor (hVDR) gene polymorphisms was evaluated in twenty human fibroblast cell lines. Genotypes at both a Fok I restriction site (F/f) in exon II and a singlet (A) repeat in exon IX (L/S) were determined, and relative transcription activities of endogenous hVDR proteins were measured using a transfected, 1,25-dihydroxyvitamin D(3)-responsive reporter gene. Observed activities ranged from 2--100-fold induction by hormone, with higher activity being displayed by the F and the L biallelic forms.

Does palliative chemotherapy palliate? Evaluation of expectations, outcomes, and costs in women receiving chemotherapy for advanced ovarian cancer.

Purpose: The value of palliative chemotherapy in women with refractory and recurrent ovarian cancer is difficult to quantify, and little is known about patient expectations from these treatments. We evaluated in the current prospective study patient expectations, palliative outcomes of chemotherapy, and the inherent resource utilization in patients undergoing second- or third-line chemotherapy for recurrent or refractory advanced ovarian cancer.

Methods: The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ C30) and Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires were used to assess palliative benefit and an in-house questionnaire was used to gauge patient expectations.

Liarozole fumarate (R85246): in the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer.

Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27).

Phase II feasibility study of sequential couplets of Cisplatin/Topotecan followed by paclitaxel/cisplatin as primary treatment for advanced epithelial ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group Study.

Purpose: Despite the improved results in advanced ovarian cancer achieved with the addition of paclitaxel to frontline therapy, there remains room for improvement. One approach is to add new agents such as topotecan. Because myelosuppression limits the delivery of topotecan with paclitaxel/cisplatin in a three-drug combination, we explored giving sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin.

Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors.

Purpose: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function.

Patients And Methods: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.

Cost-utility analysis of second-line hormonal therapy in advanced breast cancer: a comparison of two aromatase inhibitors to megestrol acetate.

Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole, to megestrol acetate (MA) in postmenopausal women with advanced breast cancer demonstrated that both agents are better tolerated than MA with comparable efficacy. In addition, one trial revealed that tumor response and time to treatment failure were significantly better with letrozole. Since oncologists are faced with a choice between three agents with at least comparable efficacy but different toxicity profiles and cost, a cost-utility analysis was conducted to quantify these differences and to determine if the new agents are more cost-effective than MA.

Liarozole fumarate (R85246): a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer.

This phase II study of liarozole fumarate (R85246, liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received > or = 2 prior hormonal therapies were treated with 150-300 mg liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response.

Characterization of unique DNA-binding and transcriptional-activation functions in the carboxyl-terminal extension of the zinc finger region in the human vitamin D receptor.

The vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D(3) and mediates its actions on gene transcription by heterodimerizing with retinoid X receptors (RXRs) on direct repeat (DR+3) vitamin D responsive elements (VDREs) located in target genes. The VDRE binding function of VDR has been primarily ascribed to the zinc finger region (residues 24-87). To define the minimal VDRE binding domain for human VDR (hVDR), a series of C-terminally truncated hVDR mutants (Delta134, Delta113, Delta102, Delta90, Delta84, Delta80, and Delta60) was generated and expressed in bacteria.