Jean Louis Misset

Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, Administered as a 24-hour Continuous Infusion in Patients With Solid Tumors

PURPOSE To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. PATIENTS AND METHODS Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 microg/m(2). RESULTS The MTD was defined as 1,800 microg/m(2) (DL 9), and the phase II RD was 1,500 microg/m(2) (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 microg/m(2)) in 94% and 25% of cycles, respectively. At the RD (1,500 microg/m(2)), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting > or = 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood. CONCLUSION The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 microg/m(2), with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.

Oxaliplatin clinical activity: a review.

Oxaliplatin (Eloxatin), a recently developed third-generation cisplatin analogue with a 1,2-diaminocyclohexane (DACH) carrier ligand, has displayed preclinical and clinical activity in a wide variety of tumour types. Synergistic with 5-FU in colorectal cancer (CRC), the combination has proven efficacy in 5-FU-resistant advanced disease and in previously untreated CRC, as demonstrated in controlled phase III trials, while evaluation in the adjuvant setting is ongoing. Due to its excellent safety profile, its unique mechanism of action and lack of cross-resistance with other active agents in CRC, oxaliplatin has also been combined with CPT-11 and Raltitrexed with promising results. Trials in pretreated and untreated advanced ovarian cancer (AOC), as a single agent or in combination with cisplatin, cyclophosphamide or paclitaxel, indicate a yet to be defined role in AOC and confirm its lack of cross-resistance with cis/carboplatin. Clinical investigations of single agent and combination therapies in breast, lung, prostate and germ-cell carcinomas, non-Hodgkins lymphoma and malignant mesothelioma are being pursued. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.

Current Issues in Adjuvant Treatment of Stage II Colon Cancer

BackgroundAdjuvant chemotherapy with 5-fluorouracil modulated by folinic acid, combined with oxaliplatin, has now become an accepted standard of care for patients with stage III colon cancer. In contrast, the use of adjuvant therapy for stage II patients remains controversial, and the identification of reliable prognostic factors to aid therapeutic decision making is crucial.MethodsThe authors critically review the results of clinical trials and meta-analyses investigating the value of adjuvant chemotherapy for stage II patients, emphasizing the heterogeneous nature of this population and the difficulty of performing clinical trials with sufficient power to reliably assess treatment efficacy. They also discuss the evidence concerning potential prognostic factors, particularly molecular markers.ResultsAvailable clinical trial data do not support the routine use of adjuvant chemotherapy for all stage II patients but suggest that it should be considered, particularly for certain high-risk patients. Recent guidelines advocate considering factors such as tumor differentiation, tumor perforation, number of lymph nodes examined, and T stage when assessing the likely benefit:risk ratio. Microsatellite instability and allelic imbalance seem to be strong predictors of good and poor prognosis, respectively, and in the near future, therapeutic decision-making models are likely to be further refined by the inclusion of such molecular markers.ConclusionsThere is growing evidence that the prognosis of certain stage II patients with unfavorable prognostic factors can be improved by adjuvant chemotherapy, and increasingly refined tools are now available to define those most likely to benefit. Referral of stage II patients for individual assessment is strongly recommended.

Recommandations pour la pratique clinique : Standards, Options : Recommandations 2008 pour la prise en charge des patientes atteintes de tumeurs épithéliales malignes de l’ovaire. Traitement médical de première ligne (rapport abrégé)

RésuméContexteLa mise à jour de ces recommandations a été élaborée conjointement par la Fédération nationale des centres de lutte contre le cancer (FNCLCC) en partenariat avec les secteurs public, privé et l’Institut national du cancer.ObjectifActualiser les recommandations établies en 2003.MéthodesL’actualisation des Standards, Options: Recommandations (SOR) repose sur une revue et une analyse critique des données scientifiques disponibles et sur le jugement argumenté des experts au sein d’un groupe de travail représentatif des modes et lieux d’exercice et des disciplines concernées par la prise en charge des patients atteints de cancer.RésultatsCet article présente les recommandations SOR 2008 relatives à la place des traitements complémentaires médicaux de première ligne et de consolidation, établies à l’issue du processus d’actualisation.AbstractContextThe Federation of French Comprehensive Cancer Centres (FNCLCC) initiated the update of these recommendations in collaboration with the French National Cancer Institute and specialists from French public universities, general hospitals and private clinics.ObjectivesTo update the recommendations established in 2003.MethodsThe guideline up-dating process is based on systematic literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Consequently, Standards, Options: Recommendations are based on the best available evidence and expert agreement.ResultsThis article presents the 2008 updated recommendations concerning medical first-line treatment and consolidation treatment of epithelial ovarian cancers.

Characterization and Multiparameter Analysis of Visual Adverse Events in Irofulven Single-Agent Phase I and II Trials

Purpose: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines. Experimental Design: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis. Results: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses ≤0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of ≤0.50 mg/kg and ≤20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms. Conclusions: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of ≤0.50 mg/kg or ≤20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.

Recommandations pour la pratique clinique : Standards, Options : Recommandations 2008 pour la prise en charge des patientes atteintes de tumeurs épithéliales malignes de l’ovaire. Traitement médical de première ligne (rapport abrégé)@@@Clinical Practice Guidelines: 2008 Update of Standards, Options: Recommendations for the management of patient with epithelial ovarian cancer — medical front-line treatment — (summary report)

RésuméContexteLa mise à jour de ces recommandations a été élaborée par la Fédération nationale des centres de lutte contre le cancer (FNCLCC) en partenariat avec les secteurs public, privé et l’Institut national du cancer.ObjectifActualiser les recommandations du chapitre «Traitement chirurgical» issu du rapport intégral validé en 1999.MéthodsL’actualisation des Standards, Options: Recommandations (SOR) repose sur une revue et une analyse critique des données scientifiques disponsibles et sur le jugement argumenté des experts au sein d’un groupe de travail représentatif des modes et lieux d’exercice et des disciplines concernées par la prise en charge des patients atteints de cancer.RésultatsCet article présente les recommandations SOR 2007 relatives au traitement chirurgical des stades précoces et des stades avancés, établies à l’issue du processus d’actualisation.AbstractContextThe French federation of comprehensive cancer centres (FNCLCC) initiated the update of these recommendations in collaboration with the French national cancer institute and with specialists from French public universities, general hospitals and private clinics.ObjectivesTo update the recommendations of the “surgical treatment” chapter in the complete report validated in 1999.MethodsThe guideline updating process is based on a systematic literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. The Standards, Options: Recommendations are thus based on the best available evidence and expert agreement.ResultsThis article presents the 2007 updated recommendations concerning the surgical treatment of early-stage and advanced-stage epithelial ovarian cancers.

Standards, Options: Recommandations pour I’indication des agents stimulant l’érythropoïèse (ASE: époétine alpha, époétine bêta et darbépoétine) dans la prise en charge de l’anémie en cancérologie (mise à jour 2007), rapport abrégé

RésuméIntroductionDès 1998, un groupe de travail d’experts, mis en place par la Fédération nationale des centres de lutte contre le cancer (FNCLCC), a publié puis a mis à jour régulièrement des recommandations pour l’indication de l’agent stimulant l’érythropoïèse (ASE) en cancérologie. À l’issue d’un processus de veille réalisé en 2006, de nouvelles données, non concordantes avec la dernière actualisation de 2003, ont été identifiées, conférant ainsi des indices suffisants pour envisager des modifications dans les recommandations existantes. Ce travail a été réalisé en collaboration avec l’Institut national du cancer et avec des partenaires des secteurs publics (CHU, CHG) et privé. Cet article présente une version abrégée du document intégral consultable sur le site Internet du programme des « Standards, Options: Recommandations » (SOR): www.sor-cancer.fr.MéthodeLa méthode d’actualisation des SOR repose sur l’analyse critique des meilleures données scientifiques disponibles et sur le jugement argumenté des experts au sein d’un groupe de travail pluridisciplinaire représentatif des modes de pratique et des disciplines concernées par la prise en charge des patients atteints de cancer. Sur la base de l’analyse de la littérature, les conclusions et leur niveau de preuve sont établis. Le niveau de preuve est fonction du type et de la qualité des études disponibles, ainsi que de la concordance ou non de leurs résultats; il est explicitement spécifié pour chacun des critères de jugement-question clinique considérés. Une recommandation est une proposition, d’une ou de plusieurs attitudes cliniques pour l’aide à la décision du professionnel de santé, destinée à améliorer la prise en charge du patient atteint de cancer. Il existe deux niveaux de gradation pour les recommandations: les Standards et les Options. Leur mise en œuvre doit tenir compte du contexte organisationnel de soin, de la situation particulière du patient et de l’expression de ses préférences. Avant publication, les RPC-SOR sont revues par des experts indépendants sélectionnés selon le même principe que le groupe d’experts rédacteurs.RésultatsLes données de la littérature sont suffisamment importantes pour mettre à jour les recommandations de 2003. Les changements suggérés par le groupe de travail sont aussi bien majeurs (reformulation ou ajout d’un Standard ou d’une Option) que mineurs (passage d’une Option en Standard). Ainsi, cinq questions cliniques ont été actualisées: l’indication de l’ASE dans le traitement curatif de l’anémie chez les patients atteints de cancer; l’indication de l’ASE dans la prévention de l’anémie chez les patients adultes atteints de cancer; l’indication de l’ASE en préopératoire; l’indication de l’ASE en oncologie pédiatrique; l’indication du fer en association avec l’ASE. À noter que pour la question clinique — indication de l’ASE en radiothérapie — les nouvelles données de la littérature ne sont pas suffisantes pour engendrer des modifications dans les recommandations initiales qui restent donc valides.ConclusionsDevant l’importance des données de la littérature publiées sur le sujet entre 2003 et 2007, il apparaît pertinent de revoir les nouvelles données dans le cadre d’un processus de veille systématique qui devra se produire en 2009.AbstractIntroductionSince 1998, a working group of specialists set up by the guidelines department (Standards, Options and Recommendations: SOR) from the National French Federation of Comprehensive Cancer Centres (FNCLCC) published then updated regularly recommendations relative to the use of ESA in anaemic patients with cancer. The systematic monitoring process realized in 2006 has permitted the identification of new data non concordant with the last actualization of 2003, conferring thus sufficient indices to consider modifications in the existing recommendations. This work was performed in collaboration with specialists from university or general hospitals and private clinics, and with the French National Cancer Institute. This article presents a short version of the updated 2007 recommendations.MethodsThis updating process is based on the methodology developed and used in the “Standards, Options, Recommendations” programme. The methodological approach combines systematic review with multidisciplinary group of experts’ judgement. On the basis of literature analysis, the conclusions and their level of evidence are established. The level of evidence is a function of the type and the quality of the studies available as well as agreement or not of their results; it is explicitly specified for each outcome-clinical question considered. A recommendation is a proposal of one or several clinical attitudes intended to improve cancer patient care. There are two levels of gradation for the recommendations: Standards and Options. Their setting takes into account the organisational context of care, the particular situation of the patient and the expression of his preferences. Before publication, the RPC-SOR are re-examined by independent reviewers selected according to the same principle as the group of experts’ writers.ResultsNew data are sufficiently important to update the last recommendations validated in 2003. Thus, five clinical questions were updated: use of ESA in anaemia treatment among adult patients with cancer; use of ESA in anaemia prophylaxis among adult patients with cancer; use of ESA in cancer patients undergoing surgery; use of ESA in children with cancer; use of iron with ESA in cancer patients. The resulting modifications were either major (new options or new standards) or minor (increased level of evidence). It should be noted that for the clinical question — use of ESA in radiotherapy — new data are not sufficient to generate modifications in the initial recommendations, which remain valid.ConclusionsBecause of the important new data published on the subject between 2003 and 2007, it appears relevant to re-examine these recommendations within a systematic monitoring process, which should be set up in 2009.