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Biomedical subjects

Pierre Fumoleau

Publications and source records attributed to Pierre Fumoleau.

36 records · Page 2Linked to original sources
PubMed2004

Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group.

PURPOSE To evaluate long-term cardiac function in patients without disease who had received six cycles of fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 50) or the same regimen with epirubicin 100 mg/m(2) (FEC 100) as adjuvant chemotherapy for node-positive breast cancer in the French Adjuvant Study Group-05 trial. PATIENTS AND METHODS One hundred fifty patients (FEC 50, n = 65; FEC 100, n = 85) who were without disease and who gave their informed consent were enrolled for long-term cardiac assessment. The assessment included cardiac events occurring after the end of chemotherapy, vital signs, concomitant disease, ECG, isotopic left ventricular ejection fraction (LVEF), and echographic parameters. Abnormal files were blindly reviewed by cardiologists and oncologists. Results The median follow-up time was 102 months. After FEC 100, LVEF was less than 50% in five patients (radioisotopic method), and two patients experienced congestive heart failure (CHF) that was possibly related to treatment. Asymptomatic left ventricular dysfunction (LVD) was experienced in 18 patients after FEC 100 and in one patient after FEC 50. In these patients, treatment causality was probable in eight patients. Two additional years after this assessment, all 18 patients were still asymptomatic. CONCLUSION After more than 8 years of follow-up, the cardiac toxicity observed after adjuvant treatment with FEC 100 comprised two cases of well-controlled CHF and 18 cases of asymptomatic LVD. In the majority of women with primary breast cancer, the benefits of treatment with FEC 100 in terms of disease-free and overall survival outweigh the risks, and cardiac risk factors should be carefully evaluated in patient selection.

Adult↗
PubMed2004

The effect of food on the pharmacokinetics of S-1 after single oral administration to patients with solid tumors.

PURPOSE: The purpose is to determine the effect of food on the bioavailability of S-1, an oral formulation of the 5-fluorouracil (5FU) prodrug Ftorafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), a dihydropyrimidine dehydrogenase inhibitor, and oxonic acid (an inhibitor of 5FU phosphoribosylation in normal gut mucosa) in a molar ratio of 1:0.4:1. EXPERIMENTAL DESIGN: Eighteen patients received a single dose of S-1 of 35 mg/m(2) with (535-885 kcal) or without food in a crossover study design: in arm A without breakfast on day -7 and with breakfast on day 0 and in arm B the reversed sequence. Blood samples were taken before and after S-1 administration. This food effect was evaluated according to the Food and Drug Administration guidelines using log-transformed data. RESULTS: Pharmacokinetic parameters for 5FU without breakfast were as follows: Tmax, 107 min; Cmax, 1.60 microm; area under the plasma concentration-time curve (AUC) 441 microm x min; and T(1/2), 104 min. Fasting decreased Tmax of FT, 5FU, CDHP, and oxonic acid significantly (P < 0.006) and increased the Cmax (P < 0.013). The food/fast ratio for the AUC of FT was not different, which for 5FU was 0.84 (P = 0.041), for CDHP was 0.89 (P = 0.191), for oxonic acid was 0.48 (P < 0.0005), and for cyanuric acid, the breakdown product of oxonic acid, was 5.1 (P = 0.019). Accumulation of uracil, indicative for dihydropyrimidine dehydrogenase inhibition, was not affected, as well as the T(1/2) of FT, 5FU, CDHP, and oxonic acid. Evaluation of the log-transformed data demonstrated that the 90% confidence interval for the food/fast ratio for the Cmax and AUC of FT, 5FU, CDHP, and uracil were within 70-143% and 80-125%, respectively, indicating no food effect. Only for oxonic acid and cyanuric acid were these values outside this interval. CONCLUSIONS: Food intake affected only the pharmacokinetics of the S-1 constituent oxonic acid but not of FT, CDHP, and 5FU. Because oxonic acid is included to protect against gastrointestinal toxicity, this observation might affect the gastrointestinal toxicity and thus the efficacy of S-1.

Administration, Oral↗
PubMed2004

Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer.

BACKGROUND: Preclinical data indicate that docetaxel, platinum salts, and the combination of both drugs are highly synergistic with the anti-HER2 antibody trastuzumab. The University of California at Los Angeles-Oncology Research Network (UCLA-ORN) and the Breast Cancer International Research Group (BCIRG) have conducted two phase II studies to evaluate docetaxel and trastuzumab in combination with either cisplatin or carboplatin for the treatment of women with advanced breast cancer that overexpresses HER2. METHODS: Each study enrolled 62 patients with HER2-overexpressing tumors. Patients received a median of six cycles of docetaxel at 75 mg/m2 of body surface area and cisplatin (BCIRG 101 study) at 75 mg/m2 or carboplatin (UCLA-ORN study) at AUC = 6 mg/mL. min given on day 1 and then every 21 days. Trastuzumab was given on day 1, cycle 1 (4 mg/kg) and then continued weekly at 2 mg/kg for 1 year or until disease progression. Tumor measurements were obtained at baseline, after three cycles of chemotherapy, and then every 3 months. HER2 gene amplification was determined by fluorescence in situ hybridization. RESULTS: Patient characteristics were comparable between trials with the exception that 15% of the patients in the UCLA-ORN study had received previous adjuvant taxane therapy. Both regimens were well tolerated, with manageable toxicities. Hematologic toxicities were more frequent in patients in the UCLA-ORN study than in patients in the BCIRG 101 study, whereas the reverse pattern was observed for non-hematologic toxicities. One patient in each study developed reversible congestive heart failure. Responses were observed in 49 of 62 patients in the BCIRG 101 study (overall response rate = 79%, 95% confidence interval [CI] = 66% to 89%) and in 34 of 59 evaluable patients in the UCLA-ORN study (overall response rate = 58%, 95% CI = 44% to 70%). Median times to progression were 9.9 months (95% CI = 8.3 to 13.1 months) and 12.7 months (95% CI = 8.6 to 15.5 months) for patients in the BCIRG 101 and UCLA-ORN studies, respectively. Overall response rates were higher and median time to progression was longer in the subset of patients whose tumors harbored HER2 gene amplification. CONCLUSION: Combinations of docetaxel, a platinum salt, and trastuzumab are feasible and active in patients with advanced breast cancers that overexpress HER2. The BCIRG is conducting ongoing randomized studies of the three-drug combination in both the metastatic and adjuvant settings.

Adult↗
PubMed2004

The vital role of education and information in patients receiving capecitabine (Xeloda).

Use of oral capecitabine (Xeloda) as home-based therapy leads to savings in healthcare resources and costs and oral chemotherapy is preferred by many cancer patients over intravenous (i.v.) 5-FU. The demands of patient management for oral therapy differ significantly from those of i.v. chemotherapy. Consequently, cancer programmes have begun to implement strategies to meet these unique demands, offer educational programmes for clinicians who prescribe capecitabine, and consider potential changes in staff responsibilities. To encourage patients to take an active part in their care, which is vital with home-based oral therapy, they must be properly informed about their treatment. Patient information needs to be specific for the cancer type and relevant for the country. Various tools have been developed, including prescription guides, diary cards and support kits, which are useful in reinforcing verbal discussions about the use of capecitabine and in helping patients to manage their treatment. Nurses have a vital role to play in encouraging the optimal use of capecitabine and prompt management of adverse events, thereby enabling the patient to achieve a better clinical outcome and maintain an improved quality of life in the home environment.

Administration, Oral↗
PubMed2004

Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer.

As an active and well-tolerated agent in the treatment of metastatic breast cancer, capecitabine (Xeloda, F. Hoffmann-La Roche, Basel, Switzerland) has the potential to confer significant clinical benefits in the primary treatment of breast cancer. The minimal myelosuppression and alopecia associated with capecitabine, together with its potential for synergistic activity with a range of other anticancer therapies, lend support to its use in combination regimens with other commonly used cytotoxic agents. Trials to date show that capecitabine combinations incorporating taxanes, vinorelbine, anthracyclines, and cisplatin are active and well tolerated in the metastatic setting. To more fully explore the clinical utility of capecitabine in early breast cancer, an extensive, worldwide phase II/III program is evaluating capecitabine as a component of adjuvant and neoadjuvant therapy. Results presented to date of the large adjuvant and neoadjuvant trials incorporating capecitabine are encouraging and suggest that women with breast cancer might benefit from the activity of capecitabine early in the disease course.

Antimetabolites, Antineoplastic↗
PubMed2004

[Cardiac dysfunction induced by trastuzumab].

Trastuzumab combined to chemotherapy had demonstrated significant improvement of time to progression and survival in metastatic breast cancer patient overexpressing HER-2. Cardiac toxicity was an unexpected side effect. The incidence of cardiac dysfunction was dependent on prior or current anthracycline exposure. The mechanism of action involved for this cardiac toxicity is unclear. We discuss in this article the incidence, the physiopathology, the risk factors, the predictive factors and the patient management and on cardiotoxicity of trastuzumab.

Antibodies, Monoclonal↗
PubMed2003

Phase I and pharmacokinetic study of E7070, a chloroindolyl-sulfonamide anticancer agent, administered on a weekly schedule to patients with solid tumors.

PURPOSE: E7070 is a sulfonamide that induces arrest at the G(1)-S boundary with subsequent dose and exposure-dependent apoptosis. The objectives of this study were (a) to determine the maximum-tolerated dose (MTD) and recommended safe dose (RD) of E7070 for additional evaluation, (b) to define the dose limiting toxicity(ies) [DLT(s)], (c) to study the pharmacokinetics of E7070, and (d) to seek preliminary evidence of antitumor activity. EXPERIMENTAL DESIGN: Patients with solid tumors who had either failed or were not amenable to established forms of treatment were eligible for the study. E7070 was administered i.v. at weekly intervals for 4 consecutive weeks to cohorts of 3-6 patients at each dose level. Treatment was repeated six weekly in the absence of tumor progression. A Fibonacci-like scheme was used for dose escalation. The MTD was determined in a stepwise procedure for two cohorts of patients; the "initial patient cohort" who met the original inclusion criteria (group A) and the "better prognosis cohort" (group B) who had adequate hepatic function, less extensive tumor involvement of the liver, and no more than three previous lines of chemotherapy. The RD was defined as the highest dose at which the incidence of definitely drug-related DLTs was <33%. The pharmacokinetic profile of E7070 was determined. RESULTS: Overall, 46 patients entered the study; information from 36 of the 37 patients forming group A was used to determine the overall MTD. An additional 9 patients plus 9 patients from group A who met the more restrictive inclusion criteria made up group B. The MTD was 500 mg/m(2)/week for both groups. Reversible neutropenia and thrombocytopenia were the most common DLTs. Other DLTs included stomatitis, hyperglycemia, sepsis, fever, hemorrhage, diarrhea, nausea, and fatigue. The pharmacokinetics of E7070 were nonlinear over the dose range 160-500 mg/m(2). One partial response was observed in a patient with an endometrial adenocarcinoma who had previously been treated with radiotherapy. Twelve other patients had stable disease as their best response (27%); among them. 1 patient with metastatic melanoma who received 21 cycles of therapy. CONCLUSIONS: The RD for further study of E7070 using this administration schedule is 400 mg/m(2)/week. Using this schedule, the predominant toxicity of E7070 is myelosuppression. E7070 has anticancer activity in pretreated patients.

Adult↗
PubMed2003

Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial.

PURPOSE: To evaluate the duration and dose intensity of epirubicin-based regimens in premenopausal patients with lymph node-positive breast cancer. PATIENTS AND METHODS: Between 1986 and 1990, 621 patients with operable breast cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75). All patients in the three arms received chest wall irradiation at the end of the third cycle. RESULTS: After a 131-month median follow-up, the 10-year disease-free survival (DFS) was 53.4%, 42.5%, and 43.6% (P =.05) in the three arms, respectively. Pairwise comparisons demonstrate that 6 FEC 50 was superior both to 3 FEC 50 (P =.02) and to 3 FEC 75 (P =.05). The 10-year overall survival (OS) for the 6 FEC 50 arm was 64.3%, for the 3 FEC 50 arm it was 56.6%, and for the 3 FEC 75 arm, it was 59.7% (P =.25), respectively. Pairwise comparisons demonstrate that 6 FEC 50 was more effective than 3 FEC 50 (P =.10). Cox regression analysis demonstrates that OS was significantly better in the 6 FEC 50 than in the 3 FEC 50 arm (P =.046). No severe infections (grade 3 to 4), acute cardiac toxicity, or deaths from toxicity have been observed. Only five patients developed delayed cardiac dysfunctions, and three patients developed acute myeloblastic leukemia. CONCLUSION: After a long-term follow-up in an adjuvant setting, the benefit of six cycles of FEC 50 compared with three cycles, whatever the dose, is highly significant in terms of DFS. As regards OS, the group receiving six cycles of FEC 50 has significantly better results than the group receiving three cycles of FEC 50.

Adult↗
PubMed2003

Phase II study of XR5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with advanced ovarian cancer.

BACKGROUND: XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of the present study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with ovarian cancer who had relapsed within 1 year after first-line chemotherapy with taxanes and platinum for advanced disease. PATIENTS AND METHODS: Patients received XR5000 at the dose of 3010 mg/m(2) through a 120-h central venous infusion every 3 weeks. Toxicity was graded according to the Common Toxicity Criteria (CTC), version 2.0. An independent panel assessed response every two cycles according to the World Health Organization (WHO) criteria. Gehan's rule was used for sample size determination. RESULTS: Sixteen patients were enrolled; one patient was ineligible because of prior melphalan single agent treatment. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (eight patients), 1 (five patients), or 2 (two patients). The 15 eligible patients received 43 cycles of XR5000 (median 2, range 1-8). Hematological toxicity was mild with only one grade 3 anemia in one patient. Other drug-related toxicities never exceeded grade 3 and included fatigue (four patients), thrombosis (one patient), nausea (one patient), stomatitis (one patient) as well as dyspnea/cough (one patient). One patient who had refused further therapy and controls after the first cycle was not assessable for response evaluation. No objective responses were observed. Four patients experienced stable disease and 10 patients progressive disease. The median time to progression was 42 days (CI 95% 40; 54). CONCLUSIONS: The complete lack of any objective response does not justify further evaluation of XR5000 in patients with advanced ovarian cancer using this dose and schedule, although the therapy was generally well tolerated.

Acridines↗
PubMed2003

Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients.

OBJECTIVE: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients. METHODS: A single dose (25-45 mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24 hr. Using NONMEM, oteracil and CDHP were analyzed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations. RESULTS: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes.

Administration, Oral↗
PubMed2003

Gemcitabine combined with docetaxel in metastatic breast cancer.

The combination of gemcitabine and docetaxel exhibits good activity in the treatment of advanced breast cancer. Phase II trial response rates using 21- or 28-day schedules have ranged from 36% to 79% in patient populations with varying degrees of pretreatment. In studies of extensively pretreated anthracycline-resistant patients, response rates have ranged from 36% to 54%, with median times to disease progression of 7 to 8 months and median survival of 12.7 to 14 months. In less treatment-experienced patients, the combination produced an overall response rate of 79%, median time to progression of 7.6 months, and median survival of 24.5 months. Toxicity has primarily consisted of neutropenia. The combination warrants additional investigation as front-line chemotherapy and in patients with anthracycline-resistant and taxane-resistant advanced disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

[Role of the combination of trastuzumab and taxanes in the therapeutic management of cancer of the breast: from preclinical data to clinical application].

Taxanes are major drugs in the treatment of breast metastatic cancer. Since 1990, the mechanisms implicated in carcinogenesis are better understood and the oncoprotein HER2 is a potential target. Trastuzumab is a monoclonal antibody that binds to this transmembrane glycoprotein. This antibody demonstrated a significant activity in clinical trials. In this review, we discuss the preclinical (mechanisms of action) and clinical data with the combination of trastuzumab and taxanes.

Antibodies, Monoclonal↗
PubMed2003

[Future perspectives. From basic research to the development of new therapies aimed at the inhibition of the different stages of signal transduction: applications in breast cancer].

The mechanism implicated in the carcinogenesis are better understood and the transduction of signal is a potential target for new agents. In this review, we describe the different pathways implicated in the transduction of signal and the potential target for new agents in breast cancer.

Antibodies, Monoclonal↗
PubMed2002

The effects of food on the pharmacokinetic profile of oral vinorelbine.

The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicentre phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/m(2) oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/m(2) was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (T(max)) was shorter in fasted patients (1.63+/-0.98 h in blood, 1.67+/-0.96 h in plasma) than in fed patients (2.48+/-1.40 h in blood, 2.56+/-1.65 h in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for C(max) and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhaematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhoea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. As the comfort of patients may be improved when the treatment is administered after a light meal, this procedure can be recommended in clinical practice.

Administration, Oral↗
PubMed2002

Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.

PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.

Administration, Oral↗
PubMed2002

[Weekly administration of paclitaxel in the treatment of metastatic breast cancer: from rational to practice].

Clinical studies showed that paclitaxel is active as single agent and in combination chemotherapy for the management of metastatic breast cancer. A variety of doses and administration schedules have been evaluated in phase II and III trials. Weekly administration of paclitaxel which is generally well tolerated increases the therapeutic index (efficacy/safety) resulting from anti-angiogenic and pro-apoptotic effects.

Antibodies, Monoclonal↗