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C Chevreau

Publications and source records attributed to C Chevreau.

At least 19 recordsLinked to original sources
PubMed1996

[Results of a randomized study comparing combination of navelbine-cisplatin to combination of vindesine-cisplatin and to navelbine alone in 612 patients with inoperable non-small cell lung cancer].

The combination of vindesine and cisplatin is considered a reference regimen in advanced NSCLC which has yielded a significant improvement in the duration of survival. A phase II study of a new semi-synthetic vinca alkaloid, Navelbine, reported an unusually high 29% response rate in stage III-IV NSCLC and a phase I-II study established the feasibility of the combination of Navelbine and cisplatin. We, therefore, designed a prospective randomized trial to compare Navelbine and cisplatin (NVB-P) to vindesine and cisplatin (VDS-P) and to evaluate whether the best of these regimens affords a survival benefit compared to Navelbine alone (NVB), an outpatient regimen. Forty-five centers included 612 patients in this study: 206 in NVB-P, 200 in VDS-P and 206 in NVB. Navelbine was given at a dose of 30 mg/m2 weekly, cisplatin at 120 mg/m2 on day 1, day 29 and then every 6 weeks and vindesine at 3 mg/m2 weekly for 6 weeks and then every other week. Treatment was continued until progression or toxicity. Patients' characteristics were similar in the three groups with 59% of patients presenting with metastatic disease. An objective response rate was observed in 30% of patients in NVB-P versus 19% in VDS-P (P = .02) and 14% in NVB (P < .001). The median duration of survival was 40 weeks in NVB-P compared to 32 weeks in VDS-P and 31 weeks in NVB. The comparison of survival between the three groups demonstrated an advantage for NVB-P compared to VDS-P (P = .04) and NVB (P = .02). Neutropenia was significantly higher in the NVB-P group (P < .001) and neurotoxicity more frequent with VDS-P (P < .004). Since our results have demonstrated that NVB-P yields a longer survival duration and a higher response rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a reference regimen in advanced NSCLC.

Adult↗
PubMed1996

[A phase II study with mitoxantrone-vinorelbine association in the treatment of advanced breast cancer in elderly women].

To assess efficacy and toxicity of less toxic analogs for advanced breast cancer in elderly women, we performed a phase II study using the combination mitoxantrone (MTZ)-vinorelbine (VNR). From January 1991 to May 1993, 25 women older than 70 years received a chemotherapy consisting in 10 mg/m2 of MTZ on day 1, followed by 20 mg/m2 of VNR on day 1 and 8. Cycles were repeated every 21 days for a maximum of ten cycles in the case of an objective response. Sixteen women previously received first line hormonotherapy, eight with only one metastatic site. Twenty-three patients are evaluable for response and toxicity. An objective response was observed in five cases (22%), with a median time to progression of 13 months. More than 75% of the planned dose-intensity, for MTZ and VNR was received by 90 and 57.2% of patients, respectively. Dose-limiting toxicity was myelosuppression but no febrile neutropenia was observed. Extra haematologic toxicities were unfrequent. This combination is well tolerated by elderly women, but best results could be achieved by increasing delivered dose intensity.

Aged↗
PubMed1995

Prediction of carboplatin clearance from standard morphological and biological patient characteristics.

BACKGROUND: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. PURPOSE: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. METHODS: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles). RESULTS: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. CONCLUSION: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

Adult↗
PubMed1995

A pharmacologically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer.

Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml-1 min.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Efficacy of lenograstim on hematologic tolerance to MAID chemotherapy in patients with advanced soft tissue sarcoma and consequences on treatment dose-intensity.

PURPOSE: This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy. PATIENTS AND METHODS: Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner. RESULTS: Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles. CONCLUSION: Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.

Adult↗
PubMed1995

[Relations between hematological toxicity and total and free plasma levels of etoposide in daily oral administration].

This study was undertaken in order to evaluate the inter- and intra-individual pharmacokinetic variabilities and their impact on the toxicity of oral Vépéside Sandoz administered daily for 21 days. The pharmacokinetic results confirmed the low bioavailability of this formulation (14% +/- 10%) and its large interindividual variability. Moreover, a great intraindividual variability was shown between day 1 and day 21. This fact can explain that the relationship between the relative decrease in neutrophil count and the pharmacokinetic parameters was observed only with either the mean area under the curve of concentrations versus time (AUC) or the mean residual concentrations (Cr). The determination of the fraction of plasma etoposide unbound, which ranged from 4.6 to 24.8%, improved the pharmacokinetic-pharmacodynamy relationship for AUC but not for Cr. This study showed the potential interest of etoposide drug monitoring. However, no dosage adjustment could be performed with this oral etoposide formulation because of its large intraindividual bioavailability. Since this study was performed, the Sandoz company withdrew this formulation, and replaced it by one identical with that available in other countries.

Administration, Oral↗
PubMed1995

[Prediction of carboplatin clearance from morphological and biological patient characteristics].

Hematologic toxicity of carboplatin is largely dependent on its pharmacokinetics. Its seems likely that therapeutic efficacy is also related to plasma drug exposure. Dosage adjustments based on isotopic determination of glomerular filtration rate have been proposed but their ambulatory use is not conceivable. A population pharmacokinetic study was undertaken to determine a relationship between patient characteristics and carboplatin clearance. Plasma carboplatin pharmacokinetics were determined as ultrafilterable platinum in 70 patients (23 to 84 years old) treated with different combination regimens including carboplatin at doses ranging from 184 to 950 mg (1-hr i.v. infusion) for various tumor types. Data were analysed using Nonlinear Mixed Effects Model (NONMEM). The data from 34 patients (46 cycles) were used to obtain the most predictive formula for the carboplatin clearance (ml/min): [formula: see text] The obtained formula was prospectively evaluated with the data from 36 other patients (43 cycles) and compared to other methods available to predict carboplatin clearance. Prospectively this formula predicted the clearance with a good precision (median absolute percent error of 10% range 0-30%) and minimal bias (median percent error: 2% range--25-30%). This method of prediction was as accurate as the one which requires the glomerular filtration rate to be measured by 51Cr-EDTA injection. This formula should allow to individualize very easily the carboplatin dosage in adults by multiplying the calculated carboplatin clearance by the area under the curve desired for administration.

Adult↗
PubMed1994

Intraoperative interstitial iridium brachytherapy in the management of soft tissue sarcomas: preliminary results of a feasibility phase II study.

Between May 1986 and June 1992, 48 patients with soft tissue sarcomas underwent 50 intraoperative interstitial implants in conjunction with conservative tumoral resections. Brachytherapy was part of the initial treatment in 27 cases and was done in 21 other previously treated patients. For the last ones brachytherapy was, in most of the cases, the only treatment in addition to surgery. The implant dose was 40-65 Gy. When combined with external irradiation the mean prescribed dose was 20 Gy (12-25 Gy). With a median follow-up of 33 months, the 3-year actuarial survival rate was 81% and the local disease-free survival 91.7%. Five local failures were observed only in patients with recurrent sarcomas: two were inside the treated volume and three outside (local failure 5/48 = 10.4%). Acute side-effects occurred in 11 patients (11/48 = 23%), with skin breakdown (two cases) infection and hematoma (one case), infection, lymphocele, secondary skin breakdown and vascular rupture (one case), infection and limited skin breakdown (two cases) and delayed healing (five cases). As a consequence, six patients required reoperation but no amputation was necessary. The functional results were good. Only three patients had a moderate limitation of movement. Late complications occurred in five patients: bone fracture (one case), leg oedemas not interfering with normal activity (three cases), peripheral neuropathy fibrosis related requiring surgery (one case). Therefore, this preliminary report shows that adjuvant intraoperative brachytherapy is feasible and is safe in treating soft tissue sarcomas, even in previously irradiated patients. However, further evaluation is needed to determine the real place of intraoperative implant in the management of soft tissue sarcomas.

Adolescent↗
PubMed1994

Modulation of cisplatin cytotoxicity by human recombinant interferon-gamma in human ovarian cancer cell lines.

Cytotoxic interactions between recombinant human interferon-gamma (IFN gamma) and cisplatin have been studied in six ovarian cell lines (IGROV1, NIHOVCAR3, SKOV3, OVCCR1, 2008 and its cisplatin resident variant 2008/C13*). Studies were performed using a cell survival assay. Results were assessed using median effect analysis. Synergy between these two drugs was observed in cell lines sensitive to IFN gamma, whatever their relative sensitivity or resistance to cisplatin, suggesting that IFN gamma enhances the cytotoxic activity of cisplatin. This interaction is not due to an increase in platinum accumulation in cells. This combination of drugs should be evaluated against human ovarian cancer xenografts in nude mice before its use in clinical practice.

Cell Survival↗
PubMed1994

High-dose interleukin-2 two days a week for metastatic renal cell carcinoma: a FNCLCC multicenter study.

The purpose of this study was to determine the efficacy and safety of a new high-dose interleukin (IL)-2 regimen, given two days a week, for renal cell carcinoma. One hundred and four patients received IL-2 as a continuous i.v. infusion for 48 h at a daily dose of 24 x 10(6) IU/m2/day for 5 consecutive weeks. Patients were assessed for efficacy 4 and 8 weeks after the end of therapy, and patients who stabilized or responded received maintenance therapy with the same regimen. An objective clinical response was observed in 20 patients (complete in four, partial in 16). The dose of infused IL2 was significantly higher in the responders than in the nonresponders (p < 0.05). Clinical responses were significantly associated with a sedimentation rate of < 20 (p = 0.02), but no other prognostic factor was identified. Mean survival was 13 months. Grade 3 and 4 toxicities were rare, except for hypotension (58% of patients), the main dose-limiting toxic effect. Overall, 83% of the planned dose of IL-2 was given. IL-2 given 2 days a week is active in metastatic renal cell carcinoma and well tolerated.

Adult↗
PubMed1993

Early intensified chemotherapy with autologous bone marrow transplantation in first line treatment of poor risk non-seminomatous germ cell tumours. Preliminary results of a French randomized trial.

UNLABELLED: For 30 months we have treated 115 non-pretreated non-seminomatous germ cell tumour (NSGCT) patients with poor risk characteristics. Patients were allocated randomly to either arm A: NCI regimen with vinblastine, etoposide (E), bleomycin and double dose cisplatin (P2) (PVeBV) 3 or 4 cycles Q3W, or arm B: modified PVeBV protocol (bleomycin in continuous infusion) Q4W than a cycle of high-dose E + cyclophosphamide + P2 (PEC) and autologous bone marrow transplantation (ABMT). 114 patients are evaluable: 81 testicular, 18 mediastinal and 15 retroperitoneal primaries. RESULTS: Arm A 57 patients: 7 patients did not complete the treatment. There were 15 failures, 9 PR, 33 CR. Seven patients relapsed. The 2-year survival is 82%. Arm B 57 patients: 16 patients did not complete the treatment. There were 26 failures, 7 PR and 24 CR. Nine patients relapsed. The 2-year survival is 60%. Both CR rates and survival are not statistically different. This trial fails to show any benefit of early intensified chemotherapy + ABMT to increase the CR and survival rates in poor risk NSGCT.

Adult↗
PubMed1993

[Continuous double administration of 5 fluorouracil (intravenous and intraperitoneal) modulated by folinic acid: phase I clinical study and pharmacokinetics in patients with intra-abdominal developing cancers].

Thirteen patients with intra-abdominal malignancies entered a phase I study of fluorouracil (5-FU) given by continuous infusion (96 h) iv and ip, simultaneously, and modulated by high-dose folinic acid-iv. Severe but reversible stomatitis was the only dose-limiting toxicity at a dose of 5-FU of 550 mg/m2/day. Local toxicity (5-FU-induced abdominal pain) was a significant side effect in patients receiving more than 1 cycle. The pharmacokinetic advantage of 5-FU-ip was confirmed in our study (ratio AUC peritoneum/plasma between 160 and 328). The systemic exposure to 5-FU (plasmatic AUC ranging from 73.4 to 173.21 microM) and to AF were found in efficacious ranges. The recommended dose of 5-FU iv and ip is 500 mg/m2/day. This regimen is feasible and may potentially have application for adjuvant chemotherapeutic programs after surgery for colorectal cancer.

Abdominal Neoplasms↗
PubMed1992

Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study.

PURPOSE: A prospective clinical study was performed to determine the incidence of high-dose continuous intravenous infusion fluorouracil (5FU-CIV) cardiotoxicity. PATIENTS AND METHODS: Three hundred sixty-seven patients who were given first-cycle high-dose 5FU-CIV were monitored for cardiac function by clinical examination, ECG, and laboratory tests. 5FU-CIV was administered during a 96- or 120-hour period at doses that ranged from 600 to 1,000 mg/m2/d. Associated drugs included cisplatin (56%), mitomycin (12.5%), folinic acid (leucovorin) (7%), and others (14%). Thirty-nine patients (10.5%) received 5FU as a single agent. RESULTS: 5FU-induced cardiac events occurred in 28 patients (7.6%; 95% confidence interval, 4.9% to 10.3%). Nine of them had a history of cardiac disease. Primary tumors included head and neck (n = 13), gastrointestinal (n = 6), breast (n = 3), and others (n = 6). The mean onset time of cardiac symptoms was 3 days (range, 2 to 5). Inaugural symptoms included angina pectoris (n = 18), hypotension (n = 6), hypertension (n = 5), malaise (n = 4), dyspnea (n = 2), arrhythmia (n = 1), or sudden death (n = 1). At 5FU discontinuation, six patients' cardiac symptoms returned to baseline, but 21 patients experienced unstable angina (n = 8), hypotension/cardiovascular collapse (n = 11), pulmonary edema (n = 1), or sudden death (n = 4). The lethality rate was 2.2% (five sudden deaths plus three irreversible collapses). ECG showed repolarization changes (ST segment deviation; T-wave inversion) in 65% and/or diffuse microvoltage in 22% of the patients who presented with cardiac events. Echocardiography showed partial or global hypokinesia in nine of the 16 patients who were examined, and one case of prolonged akinesia. Cardiac enzymes rarely showed an increase (n = 2). In severe but reversible cases, clinical, ECG, and echographic parameters returned to baseline status within 48 hours after the drug discontinuation. A fluorine 19 nuclear magnetic resonance (19F NMR) analysis of urine was performed on 14 patients; six had cardiac symptoms and eight did not. Fluoroacetate (FAC), a known cardiotoxic compound, was detected in all cases. CONCLUSION: In our study, the incidence of high-dose 5FU-CVI cardiotoxicity was 7.6%. The hypothesis of a toxic cardiomyopathic process requires further confirmation.

Adult↗
PubMed1992

Stage I cutaneous malignant melanoma: risk factors of loco-regional recurrence after wide local excision and clinical perspectives.

Two hundred and nineteen patients admitted to the Centre Claudius Regaud over a 14-year period for a stage I cutaneous malignant melanoma were retrospectively evaluated for loco-regional recurrence rates, risk factors and survival rates following wide primary excision. Five and 8 year survival rates corrected for deaths owing to concurrent illness were 77% and 73%. The loco-regional control rate was 69% (151/219). Distant metastases occurred in 59% (40/68) of patients who had a loco-regional recurrence, versus 11% (16/151) of patients when loco-regional control was obtained (P < 0.001). Multivariate analysis was used to ascertain which risk factors act independently as predictors of poor loco-regional control. Anatomical location of the primary ('head and neck-trunk-hands and feet' vs 'proximal limb') and thickness formed the best model in this respect among 11 prognostic factors studied. Since loco-regional recurrence may be associated with an increased risk of distant metastatic disease, we advocate the use of elective regional lymph node dissection in stage I patients at high risk of loco-regional recurrence in the hope that a portion of these patients may have increased survival owing to lack of development of widespread metastases.

Actuarial Analysis↗
PubMed1991

Chronopharmacokinetics of doxorubicin in patients with breast cancer.

The chronopharmacokinetics of doxorubicin (DOX) has been studied in 18 patients suffering from breast cancer. They received combined chemotherapy including DOX (50 mg/m2 as an iv bolus), given at two different times (09.00 h or 21.00 h). The two randomized courses of the protocol were given to each patient at a four week interval. The total body clearance (CL) of DOX was significantly decreased when the drug was administered at 21.00 h, resulting in a longer elimination half-life and an increase in AUC. The renal clearance of DOX did not differ at the different times of administration, and it appears that the decrease in CL was related to a change in hepatic blood flow. The volume of distribution of the drug was not changed.

Adult↗
PubMed1991

Phase I/II pharmacokinetic study of mitoxantrone by continuous venous infusion in patients with solid tumours and lymphoproliferative diseases.

Phase I and pharmacokinetic studies were performed in order to evaluate the maximum tolerated dose and the efficiency of 120 h continuous venous infusion (CVI) of mitoxantrone. 25 patients suffering from either metastatic solid tumour or refractory lymphoproliferative disease were included in the study. The starting dose was 2 mg/m2 per day and was increased by a 0.2 mg/m2 per day step dose. The main toxicity observed was leukopenia which became limiting in more than 50% of the patients receiving 2.4 mg/m2 per day (12 mg/m2 over a 120 h period); this dose was defined as the maximal tolerated dose in these pretreated patients. One partial response and three stable diseases were observed. A plasma plateau concentration of mitoxantrone (2.13 [S.D. 0.54] micrograms/1 at 2 mg/m2 per day, 2.56 [1.32] micrograms/1 at 2.2 per day and 3.46 [1.32] micrograms/l at 2.4 mg/m2 per day) was reached within 24-48 h. It was linearly related to the administered dose. The mean plasma clearance of mitoxantrone was 27.8 [14.2] l/h/m2 and the volume of distribution of the beta phase averaged 2327 [2125] l/m2. An inverse relationship was established between the mitoxantrone clearance and the degree of hematologic toxicity. This 120 h CVI mitoxantrone schedule was safe and could be repeated every 3 weeks in an outpatient setting. The relationship between mitoxantrone clearance and the drug related haematotoxicity could be used for an individual dose adjustment.

Adolescent↗
PubMed1991

Teniposide and cisplatin given by intraperitoneal administration: preclinical and phase I/pharmacokinetic studies.

Cisplatin and teniposide given by intraperitoneal (IP) route exert a synergistic therapeutic effect against ascitic P388 leukemia in mice. As single agents, they display different dose-limiting toxicities and favourable pharmacokinetic characteristics in IP phase I trials. We administered cisplatin (fixed dose: 200 mg/m2) and teniposide (escalating doses) by IP route without dwell-time to investigate the toxicity, pharmacokinetics and clinical activity of this 2-drug combination. Nine patients received a total of 14 courses. Myelosuppression, nausea and vomiting were the most frequent toxicities. Leukopenia was the dose-limiting toxicity. The maximum tolerated dose of teniposide was 100 mg/m2 when administered with a fixed dose of 200 mg/m2 cisplatin. Pharmacokinetic analysis showed that the main parameters of both cisplatin and teniposide in the peritoneum and in the plasma were not modified when the drugs were combined. It appears that a pharmacodynamic interaction exists between cisplatin and teniposide which results in increased hematologic toxicity. Although an objective response has been observed in one patient with refractory ovarian cancer, such association should not be applicable for further clinical development due to marked toxicity and the low dose of teniposide recommended.

Adult↗