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Biomedical subjects

Jérôme Fayette

Publications and source records attributed to Jérôme Fayette.

15 recordsLinked to original sources
PubMed2006

Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis.

Advanced soft-tissue sarcomas are usually resistant to cytotoxic agents such as doxorubicin and ifosfamide. Antitumor activity has been observed for gemcitabine and docetaxel combination. We conducted a retrospective study on 133 patients (58 males/75 females) with unresectable or metastatic soft-tissue sarcoma. The median age at diagnosis was 51.7 (18-82), with 76 patients with leiomoyosarcoma and 57 patients with other histological subtypes. The initial localizations were limb (44), uterine (32), retroperitoneal (23) and organs or bone (34). Patients received 900 mg/m2 of gemcitabine (days 1 and 8) over 90 min plus 100 mg/m2 of docetaxel (day 8), intravenously every 21 days. Gemcitabine/docetaxel combination was well tolerated with an overall response of 18.4% and with no clear statistical difference between leiomyosarcomas and other histological subtypes (24.2% versus 10.4% (p=0.06)). No difference was found between uterine soft-tissue sarcomas versus others. The median overall survival was 12.1 months (1-28). Better overall survival was correlated with leiomyosarcoma (p=0.01) and with the quality of the response, even for patients with stable disease (p<10(-4)). No statistical difference was found for the initial localization. Response to treatment and overall survival were better for patients in World Health Organization (WHO) performance status classification (PS) 0 at baseline versus patients in WHO PS-1, 2 or 3 (p=0.023 and p<10(-4), respectively). Gemcitabine/docetaxel combination was tolerable and demonstrated better response and survival for leiomyosarcoma, especially for patients in WHO PS-0 at baseline. For the other histological subtypes, the response was not encouraging, but the survival for patients in response or stable suggests further investigation.

Adolescent↗
PubMed2006

[Adjuvant chemotherapy in the treatment of sarcomas].

For many types of cancers, adjuvant chemotherapy showed a moderate but significant benefit in terms of survival improvement. In sarcomas, the situation is contrasted and depends on the histological, molecular sub-types, as well as the topography of the tumor. Soft tissue sarcomas are in general poorly chemosensitive tumors and while adjuvant chemotherapy was found effective to delay relapses or to decrease the local relapses, it failed to yield a significant benefit with regard to overall survival. Sub-groups analysis indicate a significant lengthening of survival for the soft tissues sarcomas of the extremities. Neoadjuvant chemotherapy of the soft tissues sarcomas starts should be reserved to rhabdomyosarcomas and the bone sarcomas like the osteosarcomas and the Ewing's sarcomas of bones are more susceptible to chemotherapy, which is an integral part of the treatment with a preoperative chemotherapy and, following surgery of the primary tumor, an adjuvant chemotherapy adapted to the histological response to the neoadjuvant treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

ET-743: a novel agent with activity in soft-tissue sarcomas.

PURPOSE OF REVIEW: ET-743 (ecteinascidin-743, trabectedin, Yondelis) is a natural marine product that has shown clinical activity in sarcoma. This paper reviews the current knowledge on this compound. RECENT FINDINGS: ET-743 interferes with several transcription factors, traps protein from the nucleotide-excision repair system, thus resulting in DNA damage, modulates gene expression, and blocks cells in the G2-M phase. In the clinical setting, after failure of standard treatment, ET-743 at 1.5 mg/m2 in 24 h continuous infusion every 21 days yielded an overall response rate close to 8% and stabilization rates of 30-40%, some lasting beyond 3 years. Leiomyosarcomas, liposarcomas, and synovial sarcomas may be the more sensitive histotypes. The major toxicities of ET-743 are hepatic--through biliary duct destruction--and hematologic. They are not cumulative and a significant number of patients may receive 12 courses or more. In a randomized Phase II study testing weekly ET-743 with treatment every 3 weeks, an improved progression-free survival rate was observed in the 3-weekly arm; the results of the follow-up Phase III trial should be available at the American Society of Clinical Oncology meeting of 2006. Phase I combination studies are in currently progress. SUMMARY: ET-743 is a novel active drug for sarcoma which yields prolonged disease-free survival in subsets of patients.

Antineoplastic Agents, Alkylating↗
PubMed2006

[News of the year 2005 in sarcomas].

This year, the innovations were numerous in sarcomas. Important progress were accomplished in the search for predictive factors which make it possible to propose to the patient a personalized treatment with the therapeutic ones reduced in the event of good prognosis or on the contrary aggressive steps in the event of bad prognosis. These prognostic factors can be genetic or clinical. Progress were also accomplished in the clinical field with the research of the most adapted therapeutic strategies and of advanced in various drugs of chemotherapy in particular the ET-743. Lastly, research is active and of many ways are tested into preclinic with a detailed attention on the way of the angiogenesis.

Antineoplastic Agents, Alkylating↗
PubMed2006

[New generation cytokines to prevent anemia and febrile neutropenia].

Febrile neutropenia and anemia are two major complications of chemotherapy. Human recombinant cytokines as G-CSF and erythropoietin allow efficient fight against these secondary effects but require iterative injections due to a short half life. The glycosylation of natural cytokines results in enhanced stability of these molecules of new generation and makes it possible to space the injections which become concomitant of chemotherapies. With regard to the erythropoietin, the prolonged half-life form shows a similar effectiveness with the natural molecule. For the G-CSF, the glycosylated form could still show itself more effective for the prevention of febrile neutropenias. Finally, these new molecules allow an improvement of the quality of life while ensuring an optimal dose-intensity of the treatment.

Anemia↗
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

Use of angiogenesis inhibitors in tumour treatment.

Advances in molecular biology have permitted the characterisation of mechanisms underlying angiogenesis. Angiogenesis is a crucial process in tumour pathogenesis as it sustains malignant cells with nutrients and oxygen. It is well known that tumour cells secrete various growth factors including VEGF, which triggers endothelial cells to form new capillaries. Preventing the expansion of new blood vessel networks results in reduced tumour size and metastases. Not surprisingly, numerous drugs that are currently under clinical development interfere with growth factor-derived angiogenic signals. This review aims to describe angiogenesis inhibitors and surveys their different modes of action.

Angiogenesis Inhibitors↗
PubMed2005

Genetic predictors for drug resistance in soft tissue sarcoma: a review of publications in 2004.

PURPOSE OF REVIEW: Sarcomas are generally managed through a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Metastatic tumor cells frequently develop resistance to cytotoxic agents. Several molecular mechanisms of drug resistance have been uncovered recently. RECENT FINDINGS: Among genes governing the apoptosis pathway, overexpression of the bcl2 family or mutations of p53 have recently been reported to be involved in drug resistance in sarcoma. The multidrug resistance genes are involved in the efflux of chemotherapeutic agents. Identification of members of this family of genes may predict resistance for developing new strategies. Several histologic subtypes of sarcomas have specific mechanisms of resistance. Methotrexate is one of the four active drugs for osteosarcoma and penetrates in tumor cell through specific carrier (reduced folate carrier) whose levels of expression or changes in amino acid sequence correlate to resistance to methotrexate. Specific molecular alteration defining nosological entities among sarcoma also correlates to drug resistance. Thirty percent of human sarcomas are characterized by specific translocations that may predict, for specific subtypes, survival and response to treatment. Finally, gastrointestinal tumors harbor specific activating mutations in KIT or PDGFRA genes, which are responsive to imatinib. Specific mutations of the KIT and PDGFRA genes have now repeatedly been found correlated to response or resistance to imatinib. SUMMARY: The molecular alterations present in tumor cells predict influence sensitivity or resistance to chemotherapy. Ultimately, this may delineate specific therapeutic strategies for both cytotoxic and targeted therapies in sarcomas.

Antineoplastic Agents↗
PubMed2003

Chemoprevention of lung cancer.

Lung cancer is a major cause of mortality and morbidity worldwide. Overall survival has only improved slightly despite advances in surgery, radiotherapy, and chemotherapy. Molecularly targeted agents are currently being studied in all treatment settings including that of chemoprevention, which is defined as the use of natural or synthetic agents to interrupt the process of carcinogenesis and to prevent or delay tumour occurrence. Lung cancer has become an increasingly difficult problem to treat with standard therapies and chemopreventive strategies have been developed. Progress in chemoprevention is reliant on the collaborative efforts of researchers in basic science and clinical settings who study the biology of lung cancer with the goal of uncovering new mechanisms of carcinogenesis. Small molecules which target specific receptors or mutations such as inhibitors of epidermal growth factor receptor or RAS will have an increasingly significant role as they are associated with more tolerable side-effects and may prove more effective. Development of a risk model with intermediate endpoints is essential for future chemoprevention studies.

Anticarcinogenic Agents↗
PubMed2003

[Overview of epidermal growth factor inhibitors (with the exclusion of ZD1839 and C225)].

The road of EGFR is an important road of initiation and progression disease. These receptors are highly expressed in the majority of tumours and this expression is associated with a poor prognostic, more aggressiveness, a poor response to treatment, and poor survival. Inhibition of EGFR is an interesting therapeutic approach. Out of ZD1839 and C225 many EGFR inhibitive agents are being evaluated in phase I, II and III trials. These agents that target the extracellular ligand-binding of the receptor include monoclonal antibodies (C225, EMD7200...) and complex ligand-toxins, others that target the intracellular ligand-binding of the receptor include small molecule tyrosine inhibitors (OS1774, ZD1839...). The results of phase I and II trials of the majority of these new agents are encouraging with a higher therapeutic index and lower toxicity than cytotoxic agents. It is necessary to confirm these results with phase II and III trials witch are now underway particularly for OS1774, EMD7200, ABX-EGF, PKI166, MD447 and ICR62.

Antineoplastic Agents↗
PubMed2003

[Therapeutic implications of epidermal growth factor receptor in lung cancer].

Lung cancer is very frequent and associated with a high mortality. In the last 25 years therapeutic progress have been limited and do not allow a 5 year global survival rate exceeding to 13-14%. Tumor biology permits a better comprehension of cancerization mechanisms and offers hope of new treatments with targeted therapies which would be specific of cancer cells and so more efficient and less toxic. Epidermal growth factor (EGF) pathway and its receptor (EGFR) expressed by most lung cancer cells is the most successfully completed example. The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal. Inhibition of this signaling pathway stops tumor growth. Several agents are in development, from preclinical studies to phase III trials. It is a matter of humanized monoclonal antibodies, such as C225 (cetuximab), targeted against EGFR, or small molecules inhibiting tyrosine kinase activity of EGFR including ZD1839 (Iressa), OS1774 (Tarceva) or CI1033, and last antisense oligonucleotides. Antibodies and small molecules are well tolerated and are responsible for limited amount of side effects, mostly cutaneous toxicity and diarrhoea. Antitumor activity has been observed in monotherapy reaching up to 25% of clinical responses in the best series. EGFR inhibition seems to be also promising in combination with chemotherapy according to the synergy observed in preclinical studies and response rate up to 50% have been reported. But phase III studies have been disappointing and additional studies are warranted before consideration for a current daily practice, mostly that severe secondary effects were reported with pulmonary toxicities. In particular it remains to explain why clinical responses do not appear correlated with EGFR expression.

Antineoplastic Agents↗
PubMedDate not supplied

ET-743: a novel agent with activity in soft tissue sarcomas.

Ecteinascidin-743 (ET-743) is a natural product derived from the marine tunicate Ectenascidia turbinate. ET-743 binds in the minor groove of DNA, blocks transcription factors activity, and traps protein from the nucleotide excision repair system, thus blocking cells in G2-M phase. ET-743 demonstrated cytotoxic activity at very low concentrations against sarcoma cell lines in pre-clinical studies. In several phase II clinical studies in patients with advanced sarcoma failing conventional doxorubicin- and ifosfamide-based chemotherapy, ET-743 delivered by continuous intravenous 24-hour infusion at a dose of 1,500 microg/m2 every 21 days yielded 8% overall response and 30%-40% stabilization rates for a clinical benefit rate close to 40%. Interestingly, long-term stabilizations over more than 3 years have been described. In vivo, ET-743 has a specific toxicity profile, the major toxicity of this product being hepatic, through biliary duct destruction, and hematologic. ET-743 has also been evaluated in first-line treatment for these patients. Finally, due to its original mode of action and the lack of cross-resistance with other chemotherapy agents, ET-743 was tested in a preclinical model in combination with other drugs. Synergy was reported in vitro with doxorubicin and cisplatin; phase I combination studies are in progress.

Antineoplastic Combined Chemotherapy Protocols↗