Melanoma: Cupissol D

Saiag P, Bosquet L, Guillot B, Verola O, Avril MF, Bailly C, Cupissol D, Dalac S, Danino A, Dréno B, Grob JJ, Leccia MT, Renaud-Vilmer C, Négrier S, Anonymous00110. · Hôpital Ambroise Paré, 92104 Boulogne, Université Versailles-Saint Quentin, France. · Eur J Dermatol. · Pubmed #17540641 links to  free full text

This publication has no abstract.

Négrier S, Saiag P, Guillot B, Verola O, Avril MF, Bailly C, Cupissol D, Dalac S, Danino A, Dreno B, Grob JJ, Leccia MT, Renaud-Vilmer C, Bosquet L, Anonymous00209, Anonymous00210, Anonymous00211, Anonymous00212, Anonymous00213, Anonymous00214, Anonymous00215, Anonymous00216. · Centre Léon-Bérard, Lyon. · Bull Cancer. · Pubmed #16714227 links to  free full text

Abstract: CONTEXT: The National French federation of comprehensive cancer centres (FNCLCC) and the French society of dermatology (SFD) initiated together the update of clinical practice guideline for the management of patients with cutaneous melanoma in collaboration with the French national cancer institute and with specialists from French public universities, general hospitals and private clinics. This work is based on the methodology developed in the "Standards, Options and Recommendations" (SOR) project. OBJECTIVES: To update SOR guidelines for the management of patients with cutaneous melanoma previously validated in 1998 and French melanoma consensus conference published by SFD and ANAES in 1995. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines have been developed, they are reviewed by independent reviewers. RESULTS: This article is a summary version of the updated clinical practice guidelines with algorithms. The main questions addressed by the expert group in this update concerned (1) The new AJCC-UICC classification (2) Excision margins (3) Sentinel node biopsy (4) Adjuvant treatments (5) Initial staging and follow up of operated patients.

Négrier S, Saiag P, Guillot B, Verola O, Avril MF, Bailly C, Cupissol D, Dalac S, Danino A, Dreno B, Grob JJ, Leccia MT, Renaud-Vilmer C, Bosquet L, Anonymous00273, Anonymous00274. · Centre Léon-Bérard, Lyon. · Ann Dermatol Venereol. · Pubmed #16521904 No free full text.

This publication has no abstract.

Négrier S, Fervers B, Bailly C, Beckendorf V, Cupissol D, Doré JF, Dorval T, Garbay JR, Vilmer C, Anonymous00212. · Centre Léon Bérard, Lyon, France. · Br J Cancer. · Pubmed #11355977 links to  free full text

This publication has no abstract.

Négrier S, Fervers B, Bailly C, Beckendorf V, Cupissol D, Doré JF, Dorval T, Garbay JR, Vilmer C. · No affiliation provided · Presse Med. · Pubmed #10923143 No free full text.

This publication has no abstract.

Négrier S, Fervers B, Bailly C, Beckendorf V, Cupissol D, Doré JF, Dorval T, Garbay JR, Vilmer C. · FNCLCC, Standards, Options, Recommandations, 101, rue de Tolbiac, 75654 Paris Cedex 13. · Bull Cancer. · Pubmed #10705288 links to  free full text

Abstract: CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the management of patients with cutaneous melanoma. METHODS: Data have been identified by literature search using Medline - until December 1998 - and the personal reference lists of the expert group. Once the guidelines were defined, the document was submitted for review to national and international independent reviewers and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the management of cutaneous melanoma (CM) are: 1) The primary prevention of melanoma is based on a reduction in exposure to ultraviolet rays (solar or artificial). 2) The diagnosis of CM requires the surgical removal and histological examination of the lesion (standard). 3) The pathological report must include the diagnosis of primary malignant melanoma, the maximum thickness of the tumour in millimeters (Breslow), the clearance of surgical margins, the level of invasion (Clark), the presence and extension of regression and the presence of any ulceration (standard). 4) The standard treatment of a primary melanoma without lymph node involvement is based on surgery that must ensure adequate margins depending on the thickness of the tumour (standard, level of evidence B). 5) After surgery of a stage I melanoma, there is no indication for additional treatment outside a prospective therapeutic study (standard, level of evidence B, French Consensus Conference). 6) For a local recurrence without node involvement, in the absence of other metastases, surgical excision is the standard treatment. 7) In the case of metastatic regional lymph nodes, a complete regional lymphadenectomy is required. There is no indication for additional treatment outside a prospective therapeutic study (standard, level of evidence B). The inclusion of these patients in controlled studies of immunotherapy is recommended. 8) There is no standard therapeutic strategy for metastatic melanoma. Conventional palliative treatment is chemotherapy with dacarbazine (level of evidence B). 9) Follow-up is based on physical examination (standard). Patient information must encourage self-surveillance. Clinical surveillance and self-detection are indicated in all cases throughout life (standard).

Guillot B, Khamari A, Cupissol D, Delaunay M, Bedane C, Dreno B, Picot MC, Dereure O. · Department of Dermatology, Hôpital Saint-Eloi, University of Montpellier I, Montpellier, France. · Melanoma Res. · Pubmed #18337651 No free full text.

Abstract: Metastatic melanoma treatment remains disappointing, and a combined approach by chemotherapy and immunotherapy might increase the response rates through a synergistic action. Accordingly, a clinical trial using oral temozolomide (TMZ) and subcutaneous PEG-interferon alpha-2b (PEG) in patients with metastatic melanoma was designed to determine the maximal tolerated dosage of both drugs and the antitumoral response. A multicenter, prospective, phase I/II study was conducted in 31 metastatic melanoma patients, without cerebral metastasis. Dose escalation was performed according to the modified continual reassessment method scale and resulted in four cohorts of patients: TMZ 150 mg/m2 5 days/week each 4 weeks and PEG 0.5 microg/kg/week - TMZ 150 mg/m2 5 days/week and PEG 1.0 microg/kg/week - TMZ 200 mg/m2 5 days/week and PEG 0.5 microg/kg/week - TMZ 200 mg/m2 5 days/week and PEG 1.0 microg/kg/week. Patients received a maximum of six cycles. Thirty-three patients were enrolled in this study: one in the first dose level, one in the second one, 18 in the third one and 11 in the fourth one. At level 4, four of 11 patients experienced dose-limiting toxicity and four nondose-limiting toxicity; toxicity was mainly hematologic (grade IV thrombocytopenia). An objective response was observed in five patients (two complete response and three partial response) receiving level 3 or 4 of treatment. The disease remained stable in three patients, and six of 31 patients were alive 24 months after enrollment. The association of oral TMZ with subcutaneous PEG in metastatic melanoma displayed an unacceptable hematological toxicity with the dosages of 200 mg/m2 5 days/week and 1 microg/week, respectively. At a lower level, this treatment was effective and deserves further investigations to define its indications in metastatic melanoma patients.

Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Nguyen BB, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre J, de Gislain C, Bensadoun JR, Clavel M. · Centre hospitalier Lyon-Sud, service de radiothérapie-oncologie, EA 643, 69495 cedex, Pierre-Bénite, France. · Cancer Radiother. · Pubmed #12648711 No free full text.

Abstract: PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.

Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M. · Centre Hospitalier Lyon Sud, Service de Radiothérapie-Oncologie, Pierre-Benite Cedex, France. · Melanoma Res. · Pubmed #12569292 No free full text.

Abstract: The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.

Dorval T, Négrier S, Chevreau C, Avril MF, Baume D, Cupissol D, Oskam R, de Peuter R, Vinke J, Herrera A, Escudier B. · French Cancer Centers' Immunotherapy Group, Institut Curie, Paris. · Cancer. · Pubmed #10091789 links to  free full text

Abstract: BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma. METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy. RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment. CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups.

Passagne I, Evrard A, Depeille P, Cuq P, Cupissol D, Vian L. · Department of Toxicology, EA 2994, School of Pharmacy, Montpellier I University, 15, Avenue Charles Flahault BP 14491, 34093 Montpellier Cedex 05, France. · Toxicol Appl Pharmacol. · Pubmed #16039682 No free full text.

Abstract: Alkylating agents play an important role in the chemotherapy of malignant melanomas. The activity of alkylating agents depends on their capacity to form alkyl adducts with DNA, in some cases causing cross-linking of DNA strands. However, the use of these agents is limited by cellular resistance induced by the DNA repair enzyme O(6)-methylguanine DNA-methyltransferase (MGMT) which removes alkyl groups from alkylated DNA strands. To determine to what extent the expression of MGMT in melanoma cells induces resistance to alkylating agents, the human cell line CAL77 Mer- (i.e., MGMT deficient) were transfected with pcMGMT vector containing human MGMT cDNA. Several clones expressing MGMT at a high level were selected to determine their sensitivity to chemotherapeutic drugs. Melanoma-transfected cells were found to be significantly less sensitive to nitrosoureas (carmustine, fotemustine, streptozotocin) and temozolomide with an increase of IC(50) values between 3 and 14 when compared to parent cells. No difference in cell survival rates between MGMT-proficient and -deficient cells was observed for melphalan, chlorambucil, busulphan, thiotepa and cisplatin which preferentially induce N(7) guanine lesions. Surprisingly, MGMT overexpression increased the sensitivity of CAL77 cells to mitomycin C by approximately 10-fold. Treatment of clonal cell lines with buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase which depletes cellular glutathione, completely reversed this unexpected increase in sensitivity to mitomycin C. This observation suggests that glutathione is involved in the sensitivity of MGMT-transfected cells to mitomycin C and may act synergistically with MGMT via an unknown mechanism.

Depeille P, Cuq P, Mary S, Passagne I, Evrard A, Cupissol D, Vian L. · Laboratoire de Toxicologie du Médicament - EA 2994, Montpellier, France. · Mol Pharmacol. · Pubmed #15044619 links to  free full text

Abstract: Previous studies have shown that glutathione S-transferases (GSTs) can operate in synergy with efflux transporters, multi-drug resistance proteins (MRPs), to confer resistance to several carcinogens, mutagens and anticancer drugs. To address the poorly documented role of the GSTM1 in cancer chemoresistance, we used CAL1 human melanoma cells expressing no endogenous GSTM1 and a high level of MRP1. Cells were transfected with an expression vector containing the GSTM1 cDNA, and different clones were selected expressing different levels of GSTM1 (RT-PCR, Western blot, and enzyme activity). Cells overexpressing GSTM1 displayed a 3- to 4-fold increase in resistance to anticancer drugs vincristine (VCR) and chlorambucil (CHB) in proliferation, cytotoxic, and clonogenic survival assays. Inhibitors of MRP1 (sulfinpyrazone, verapamil) and GST (dicumarol, curcumin) completely reversed the GSTM1-associated resistance to VCR, indicating that a MRP efflux function is necessary to potentiate GSTM1-mediated resistance to VCR. Conversely, MRP1 inhibitors had no effect on the sensitivity to CHB. Using immunofluorescence assay, GSTM1 was also shown to protect microtubule network integrity from VCR-induced inhibition of microtubule polymerization. In conclusion, these results show that GSTM1 alone is involved in melanoma resistance to CHB, whereas it can act in synergy with MRP1 to protect cells from toxic effects of VCR.

Passagne I, Evrard A, Winum JY, Depeille P, Cuq P, Montero JL, Cupissol D, Vian L. · School of Pharmacy, Department of Toxicology, Montpellier I University, 15 avenue Charles Flahault BP 14491, 34093 Montpellier Cedex 05, France. · J Pharmacol Exp Ther. · Pubmed #12970393 links to  free full text

Abstract: Fotemustine is a third generation chloroethylnitrosourea that has demonstrated significant antitumoral effects in malignant melanoma. However, its use is somewhat limited by its toxic side effects and chemoresistance caused by direct repair of O6-alkyl groups by the enzyme O6-methylguanine DNA-methyltransferase (MGMT). The aim of this work was to determine to what extent the expression of MGMT influences cytotoxicity, DNA damage, and apoptosis induced by new nitrososulfamide analogs of fotemustine (compounds 4 and 8), which have previously demonstrated interesting antiproliferative properties. We carried out complementary strategies that consisted of MGMT cDNA transfection in CAL77 Mer- melanoma cells and of MGMT inhibition with O6-benzylguanine (BG) in A375 Mer+ melanoma cells. MGMT-transfected cells were 7 to 9 times less sensitive to fotemustine than parent cells, whereas no difference between the transfected and parent cells was observed for nitrososulfamide analogs. The cytotoxicity of these analogs vis à vis a MGMT-proficient A375 melanoma cell line was approximately 3 times greater than that of fotemustine. Coincubation of these cells with O6-benzylguanine significantly increased the cytotoxicity of fotemustine and compound 8, whereas BG had little effect on the cytotoxicity of compound 4. Furthermore, DNA fragmentation determined by a comet assay was greater with nitrososulfamide analogs than with fotemustine. O6-benzylguanine increased DNA fragmentation for fotemustine and compound 8, but not for compound 4, which induced comets with a typical apoptotic appearance. The ability of this compound to induce apoptosis in the absence of BG was confirmed by a specific enzyme-linked immunosorbent assay apoptotic assay using a single-stranded DNA monoclonal antibody.