Biomedical subjects

Florence Duffaud

Publications and source records attributed to Florence Duffaud.

14 recordsLinked to original sources

PubMed2006

Brostallicin, an agent with potential activity in metastatic soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

The study aimed to assess the efficacy and safety of brostallicin, a new DNA minor groove binder, at a dose of 10mg/m2, intravenous (i.v.) every three weeks, in patients with advanced or inoperable soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) failing first line therapy. Two groups were recruited: (1) GIST following treatment with imatinib; (2) other STS following treatment with single agent doxorubicin or ifosfamide or a single line of combination therapy. The primary end-point was overall response rate (ORR) as defined by response evaluation criteria in solid tumours (RECIST). Progression free survival (PFS) was a secondary end-point. In the GIST group, a Simon two step design was planned: first step 18 patients, total 32 patients (p1=20% p0=5% alpha=beta=0.1). In the non-GIST group, planned sample size was 40 in a standard Fleming one-step design (p0=10%, p1=25%, alpha=beta=0.1). Forty-three patients with non-GIST and 21 patients with GIST were recruited. In general, the drug was well tolerated. Common Toxicity Criteria (CTC) grade 3 or grade 4 toxicity was granulocytopenia: 70% of patients, 50% of cycles; fatigue: 25% of patients, 8% of cycles; febrile neutropenia: 14% of patients, 4% of cycles. There was one confirmed toxic death due to neutropenic septicaemia. Three patients had clinically significant allergic reactions in 249 cycles delivered. In the GIST group, no patients had a confirmed response and recruitment was discontinued at the first step. In the non-GIST group, there were two confirmed partial responses. The 3 month PFS was 46% in the non-GIST group and 33% in the GIST group. In the non-GIST group, this PFS is in the range of other agents considered active in STS, and may predict for more substantial first line activity. Further investigation in STS other than GIST appears warranted.

Adult↗

PubMed2006

Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer patients based upon total platinum measurement in plasma.

Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)/pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma. Nineteen patients (66 therapeutic courses) were treated with platinum-based combinational therapy. Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent prospective dose adjustment in order to reach a target Cmax (Cend) of 1.95 mg/L of total platinum. Performance of the Bayesian dosing method was evaluated by comparing target Cmax with achieved Cmax. The mean+/-SD Cmax achieved was 1.93+/-0.16 mg/L. No statistically significant difference was observed between experimental and target values (P>0.05, t test), and Cend achievement was done with an overall 6.6% precision, a performance to be compared with the initial 54% interpatient variability observed in CDDP clearance. A nonlinear mixed effect model population PK analysis was subsequently performed to identify retrospectively the covariates associated with PK parameters of total CDDP. It showed a good correlation (r=0.84, P=0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r=0.59) was found between BSA and total CDDP clearance and, importantly, no additional relationship was established with BSA when successive therapeutic courses, and not only the first one, were considered. This highlights the critical importance of total drug accumulation on CDDP pharmacokinetics when several infusions are to be administered in a row and, therefore, the need for real-time dose individualization that takes into account the course number, rather than BSA. Finally, doses of CDDP administered during each course were significantly higher (+20%, P<0.01) than the ones classically normalized with BSA, thus leading to an overall greater drug exposure in the patients. It is noteworthy that despite these markedly higher doses, little severe toxicity was reported, and all of the patients presented in this study were still alive and disease free after a follow-up of up to 15 years.

Adult↗

PubMed2006

Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60% higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.

Aged↗

PubMed2006

A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy.

Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.

Adult↗

PubMed2006

[Neoadjuvant chemotherapy in sarcoma].

This document describe s the proposed clinical practices guidelines for neoadjuvant chemotherapy in soft tissue sarcomas proposed by the French Sarcoma Group.Neo-adjuvant chemotherapy remains an experimental therapeutic procedure in soft tissue sarcomas. Neo-adjuvant chemotherapy may be proposed in three different types of situations: 1) a locally advanced tumor, non accessible to R0 or 1 removal of the lesion. Its objective is there to allow for R0 or R1 surgical removal of the tumor. 2) A locally advanced tumor, accessible to R0 or 1 removal of the lesion, but with a mutilating surgery (amputation). Its objective is there to allow for R0 or R1 conservative surgical removal of the tumor. In both situation, the strategy should be discussed beforehand in a multidisciplinary specialized consultation for sarcoma. 3) In the case where complete (R0 or R1) surgical removal of the tumor can be performed, neooadjuvant chemotherapy has no demonstrated role. The only randomized phase III clinical trial testing neo-adjuvant chemotherapy in this setting, i.e. the STBSG 62871 STBSG trial, failed to demonstrate any benefit in terms of overall or progression free survival. The selection of the type of chemotherapy regimen given in the neoadjuvant setting should be discussed in a multidisciplinary setting, considering the age and the general status of the patient; young patients, without associated concomittent illnesses should be proposed for a combined chemotherapy regimen, combining doxorubicin (> or = 50 mg/m2) and ifosfamide (> 5 g/m2) on the basis of randomized trials demonstrating an improvement of response rate versus single agent therapy with doxorubine. In elderly and/or frail patients, conversely, single agent doxorubicin may be the preferred option.

Antineoplastic Agents↗

PubMed2005

[Recommendations for the management of GIST patients].

BACKGROUND: The management of gastrointestinal stromal tumors (GIST) has evolved very rapidly in the last years. A national consensus meeting was therefore organized in order to identify the optimal management procedures for patients with GIST in localized and advanced stages. METHODS: A panel of different specialties, including pathology, molecular biology, imaging, surgery, gastroenterology, medical oncology reviewed the current literature, in particular the recent Lugano conference, to identify consensus points and topics for future research in four different working groups: pathology and molecular biology, early management of small tumors and imaging, surgery, and medical treatment. Consensus points were categorized according to the Standard Options Recommendations (SOR) of the French Federation of Cancer Centers. RESULTS: The standard histological examination with immunohistochemical analysis using CD117, CD34, PS100, desmin and smooth muscle actin is considered standard. Molecular biology for the identification of KIT and PDGFRA mutation is advisable for GIST with negative CD117 staining, and otherwise is considered a research procedure. Complete tumor resection with negative tumor margins is the standard surgical treatment. Adjuvant imatinib after optimal tumor resection as well as neo-adjuvant imatinib remain experimental approaches to be performed within prospective clinical studies. Imatinib should be started at the date of diagnosis of metastatic relapse and given until development of intolerance or progressive disease. Resection of metastases is also considered as an experimental procedure which can not be recommended routinely. The criteria for tumor response to imatinib should include not only tumor size reduction or disease stabilization, but also reduction of tumor density (Hounsfield units) on computed tomography, metabolic activity (i.e. reduction of FDG uptake on positron emission tomography), and reduction of vascularisation of the tumors using contrast enhanced ultrasound evaluation. An increase in tumor size may be associated with pathologic response to imatinib therapy, and available survival data indicate that the survival of these patients is similar to that of patients with conventional tumor response. CONCLUSIONS: Consensus points in clinical management of GIST in this national conference adopted the majority of consensus points published in the Lugano conference. This multidisciplinary work will be published in the reference oncology, gastroenterology, and pathology journals in French languages.

Antineoplastic Agents↗

PubMed2004

[Impact of a brochure on pain destined for thoracic oncology patients].

OBJECTIVE: To assess the impact of a brochure supplied on pain and analgesic treatment on the knowledge, attitude, belief and perception of patients consulting oncology departments. METHOD: A prospective, comparative, study on patients consulting a thoracic oncology and a general oncology department, suffering from pain and motivating a treatment level > or = to 2 (WHO scale). A group of patients having been given a brochure (case) was compared with a group who had not been given the brochure (controls). The assessment questionnaire, developed according to the KABP (Knowledge, Attitudes, Belief, Practice) method, was distributed to the 2 groups. A second assessment was made 4 weeks after the patients having received the brochure. Visual analog scales (VAS) followed the intensity of the pain. RESULTS: Twenty-one cases and 33 controls were assessed. There was no modification in their belief (risk of addiction) but an improvement in their knowledge (duration of action of morphine agents, management of treatment, multi-disciplinary management). This improvement in knowledge was accompanied by improved control of pain: 2/3 of the patients exhibited a VAS < 1 at the time of the second assessment versus 1/3 during the initial assessment. CONCLUSION: Improvement, if only partial, in the patients' knowledge of pain and its treatment using a brochure, is one of the routes for optimising the management of pain.

Female↗

PubMed2004

[A study of the social representations in chemotherapy: a way to analyse the relations between patients and oncologists].

This research aims to study social representations throughout chemiotherapy, out of a population composed of doctors specialized in Oncology on one hand, and patients dealing with cancer during their chemiotherapy on the other hand. Our methodology is situated among quantitative methods using SPSS for Anovas to analyze statistics datas, EVOQ and Alceste for the pragmatic analysis of the discourse. The datas were collected from a questionnaire including items and words associations. We were interested in chemiotherapy which appears as a social object likely to generate a representative process from which emerges a serie of adaptative strategies belonging to both cognitivo-behaviourism and emotional spheres. chemiotherapy leads to an adaptation of the patient and remains a mediator in the doctor-patient's relation. As far as representations are "action guides", the existence of a representation specific to patients and doctors, allowes us to point out, through a semantic and emotional gap a technical medicine which is, in the future, likely to tend to existentialism.

Antineoplastic Agents↗

PubMed2003

Gastrointestinal stromal tumors: biology and treatment.

Scientific knowledge on gastrointestinal stromal tumors (GIST) has dramatically progressed over the last 10 years. During this period, this distinct disease entity was identified under various acronyms (GIST remaining the most commonly used), the molecular basis of disease transformation (i.e. activating c-KIT mutations) was identified in sporadic and familial cases, and finally GIST was identified as the sarcoma subtype most resistant to chemotherapy in both retrospective and prospective studies. Until 2000, surgery was the only reported efficient treatment modality in this disease, both in the localized and metastatic phase. In 2000, the first GIST patient received Glivec, and in the last 3 years, more than 2,000 patients were included in prospective trials evaluating this compound in advanced phases. Disease control is initially achieved in 80-90% of patients, with only 10-15% of patients dying in the first year following the occurrence of metastases, while the median overall survival was less than 12 months with previous treatment options. However, there still remain several questions regarding long-term outcome, tolerance, cure, dose of Glivec, and alternative treatment upon relapse of GIST in patients receiving Glivec. Additional follow-up is necessary. Glivec treatment of GIST is the first example of an efficient targeted treatment in a solid tumor.

Antineoplastic Agents↗

PubMed2003

CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas. Correlations between immunohistochemical analysis and long-term follow-up in a series of 929 patients.

CD105 (endoglin) is expressed significantly in activated endothelial cells in culture and in tumor microvessels. Quantification of CD105 immunocytochemical expression that may be clinically relevant has not been accurately evaluated. We studied CD105 expression on frozen tissue sections by using immunohistochemical assays in a series of 929 patients and correlated the findings with long-term follow-up (median, 11.3 years). Univariate (Kaplan-Meier) analysis showed that the number of CD105+ microvessels (cutoff, 15 vessels) correlated significantly with poor overall survival among all patients (P = .001). This correlation was less significant in node-negative patients (P = .035). Marked CD105 expression also correlated with a high risk for metastasis among all patients (P = .006) and among node-negative patients (P = .001). Multivariate analysis (Cox model) identified CD105 immunodetection as an independent prognostic indicator. Our results suggest that immunohistochemical expression of CD105 has practical clinical relevance for identifying node-negative patients with a poor prognosis. Moreover, immunodetection of CD105 also may be considered a potential tool for selecting patients who could benefit from specific antiangiogenic therapy, using anti-CD105 conjugates.

Adult↗

PubMed2003

Tie2/Tek expression in breast carcinoma: correlations of immunohistochemical assays and long-term follow-up in a series of 909 patients.

The degree of angiogenesis in breast cancer has previously been shown to be an indicator of prognosis, and tumor microvasculature is at present a candidate target for new antiangiogenic therapies. Tie2/tek receptor tyrosine kinase is a novel marker of microvasculature of solid tumors that appears to play a key role in the angiogenesis process in breast cancer. However the prognostic significance of Tie2 has never been demonstrated in this neoplasm. In order to establish the prognostic value of Tie2 in breast carcinoma, we investigated Tie2 expression in a large series of patients and correlated it with long-term follow-up. Tie2 expression was investigated using immunohistochemical assays with a polyclonal antibody on frozen sections in a series of 909 patients, and was correlated with long-term (median, 11.3 years) follow-up. Univariate (Kaplan-Meier) analysis showed that a large Tie2 positive tumor surface (cut off = 7%) was significantly correlated with poor overall survival (p=0.025). Tie2 expression correlated with high metastasis risk among all patients (p=0.00067) and among node negative ones as well (p=0.01). Tie2 immuno-expression was also significantly predictive of relapse in all patients (p=0.003) and in the node negative subgroup (p=0.02). In multivariate analysis (Cox model) Tie2 immunodetection was identified as an independent prognostic indicator. Our results suggest that Tie2 immunohistochemical expression exhibits practical clinical relevance in terms of prognostic prediction. Tie2 expression permits identification of poor outcome patients, in particular node negative ones with high risk of metastasis and relapse. Tie2 immunodetection may further be considered as a potential tool for selecting patients who could benefit in the future from specific antiangiogenic therapy interfering with Tie2 pathway.

Adult↗

PubMed2003

[Prognostic significance of VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in breast carcinoma].

OBJECTIVES: The aim of this study was to investigate the prognostic value of vascular endothelial growth factor (VEGF) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in breast carcinoma. METHODS: VEGF receptor expression was investigated using immunohistochemical assays with monoclonal antibodies on frozen sections in a series of 918 patients and was correlated with prognostic parameters and with long-term follow-up (median, 11.3 years). VEGFR-1 and VEGFR-2 immunostained surface was evaluated in percentage of the total tumor specimen surface by light microscopy (x100). RESULTS: VEGFR-1 and VEGFR-2 were strongly expressed in endothelial cells within blood microvessels, and weakly in tumor cells. Univariate (Kaplan Meier) analysis showed that VEGFR-1 positive tumor surface (cut off=5%) was not correlated with survival, but was significantly correlated with high metastasis risk (p=0.03) and relapse (p=0.01) in all patients, and in those with node negative tumors (p=0.001 and p=0.01 respectively). In multivariate analysis (Cox model), VEGFR-1 expression was identified as an independent prognostic indicator. Univariate analysis showed that VEGFR-2 positive tumor surface (cut off=10%) was not correlated with survival or with metastasis risk and relapse. CONCLUSION: Our results show that VEGFR-1 immunohistochemical expression permits the identification of patients with poor outcome, particularly those with node negative tumors, with high risk of metastasis and relapse. VEGFR-1 immunodetection may further be considered as a potential tool for evaluating tumor agressiveness and therapeutic strategies in breast cancer.

Adult↗

PubMed2002

Population pharmacokinetics of etoposide: application to therapeutic drug monitoring.

Antineoplastic agent etoposide (VP16) displays narrow therapeutic index and erratic pharmacokinetics, and dose individualization is a convenient way for overcoming the interpatient variability, so as to maintain the drug exposure within a therapeutic range. The authors proposed a population-based Bayesian methodology to adjust routinely VP16 dosage when given as a 5-day infusion. The mean VP16 pharmacokinetic parameters of the reference population calculated from 14 patients following the two-stage method were CL = 1.92 +/- 0.512 L/h and t(1/2) = 6.7 +/- 2 hours. The reference population was next used prospectively for Bayesian dose individualization for 25 patients (47 courses) undergoing 5-day infusions of VP16. Resulting steady-state concentrations proved to be successfully adjusted to the target values in 77% of the courses. Therefore, the method presented here meets the requirements for routine therapeutic drug monitoring of VP16, a major anticancer drug extensively used in clinical oncology.

Adult↗

PubMed2002

[Interest of studying the in vitro genotoxicity of an antineoplastic drug on healthy human cells: paclitaxel example].

Paclitaxel is often used as an adjuvant antineoplastic agent. However, very little data is available in literature on its potential genotoxicity on healthy human cells. Our objective is to study the potential in vitro genotoxicity of paclitaxel, by using the cytokinesis-blocked micronucleus assay in combination with fluorescent in situ hybridization of nonspecific centromeric probes on human T-lymphocytes. Paclitaxel was found to significantly increase the micronucleated lymphocyte rates with a concentration-dependant manner. This increase is observed as early as with the weakest concentration tested (2,5 nM). Over 85% of those micronuclei contained one or more whole chromosomes, indicating that paclitaxel is a strong aneugenic drug. Paclitaxel induces the formation of aneuploid daughter cells, as a consequence of abnormalities in the distribution of chromosomes during the cell division. However, aneuploidy is probably one of the first events in the oncogenesis process, and it often seems to be linked to a dysfunction of the centrosome. An interaction between paclitaxel and centrosome could explain a considerable amount of the centromere-positive micronuclei due to multipolar mitosis. Paclitaxel, whose influence is being questioned in clinical practice in the occurrence of secondary acute myeloid leukemia, is therefore an in vitro aneugenic drug, which could be carcinogenic.

Aneuploidy↗