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Accueil Nota Bene Cancer V2 Numéro 134 du 03 Mai 2012 Traitements

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Nota Bene Cancer Numéro 134 du 03 Mai 2012 RSS

Traitements

Traitements localisés : découverte et développement

Menée sur 14 patientes atteintes d'un cancer primitif du sein (durée de suivi : 6 mois), cette étude prospective évalue l'effet de deux techniques chirurgicales de curage axillaire sur la morbidité post-opératoire

  • Axillary dissection in primary breast cancer : variations of the surgical technique and influence on morbidity
    Cancer Management and Research, Vol. 4 (1), pp. 121-127, 2012 (résumé)
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    Menée sur 14 patientes atteintes d'un cancer primitif du sein (durée de suivi : 6 mois), cette étude prospective évalue l'effet de deux techniques chirurgicales de curage axillaire sur la morbidité post-opératoire

    “Axillary dissection in primary breast cancer : variations of the surgical technique and influence on morbidity”

    • Wojcinski S, Nuengsri S, Hillemanns P, Schmidt W, Deryal M, Ertan K, Degenhardt F

    Lymphedema of the arm is the most common and impairing complication after breast cancer surgery with axillary lymph node dissection (ALND). Our prospective study evaluated the effect of two different surgical techniques for ALND on postoperative morbidity. Patients were scheduled to undergo ALND. Patients in group 1 (n = 17) underwent the most common and standard technique of ALND, which uses sharp dissection of the tissue and subsequent electrocoagulation of bleedings. Patients in group 2 (n = 17) underwent a modified standard technique of ALND with clamping and ligatures of all resection margins. Postoperative wound secretion was quantified and patients were followed up for 6 months to assess long-term morbidity. The variations in surgical technique had no significant influence on the outcome variables. However, patients in group 2 showed a tendency to less wound secretion (713 versus 802 mL; P = nonsignificant), a decreased rate of immediate postoperative seromas (11.8 versus ...


Mots clés : Sein; Traitements (Traitements localisés : découverte et développement)

Mené sur une cohorte de 226 patientes atteintes d'un cancer du sein présentant un risque faible de récidive (durée moyenne de suivi : 46 mois), cet essai monocentrique de phase II évalue l'efficacité et la toxicité d'une irradiation partielle et accélérée du sein par rayonnements électromagnétiques durant l'intervention chirurgicale

  • Accelerated Partial Breast Irradiation Using Only Intraoperative Electron Radiation Therapy in Early Stage Breast Cancer
    International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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    Mené sur une cohorte de 226 patientes atteintes d'un cancer du sein présentant un risque faible de récidive (durée moyenne de suivi : 46 mois), cet essai monocentrique de phase II évalue l'efficacité et la toxicité d'une irradiation partielle et accélérée du sein par rayonnements électromagnétiques durant l'intervention chirurgicale

    “Accelerated Partial Breast Irradiation Using Only Intraoperative Electron Radiation Therapy in Early Stage Breast Cancer”

    • Maluta, Sergio;Dall'oglio, Stefano;Marciai, Nadia;Gabbani, Milena;Franchini, Zeno;Pietrarota, Paolo;Meliadò, Gabriele;Guariglia, Stefania;Cavedon, Carlo

    We report the results of a single-institution, phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiation therapy (IOERT) in patients with low-risk early stage breast cancer. A cohort of 226 patients with low-risk, early stage breast cancer were treated with local excision and axillary management (sentinel node biopsy with or without axillary node dissection). After the surgeon temporarily reapproximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed, with a margin of 2 cm laterally. With a mean follow-up of 46 months (range, 28-63 months), only 1 case of local recurrence was reported. The observed toxicity was considered acceptable. APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer in carefully selected patients. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole-breast ...


Mots clés : Sein; Traitements (Traitements localisés : découverte et développement)

Traitements localisés : applications cliniques

Menée sur 285 hommes atteints d'un cancer localisé de la prostate présentant un risque élevé de récidive ( score de Gleason de 8 à 10) et traité entre 1988 et 2008 (durée médiane de suivi : 4,62 ans), cette étude évalue la mortalité spécifique associée à une prostatectomie radicale, combinée ou non à une brachythérapie, par rapport à une radiothérapie et à un traitement anti-androgénique

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    Menée sur 285 hommes atteints d'un cancer localisé de la prostate présentant un risque élevé de récidive ( score de Gleason de 8 à 10) et traité entre 1988 et 2008 (durée médiane de suivi : 4,62 ans), cette étude évalue la mortalité spécifique associée à une prostatectomie radicale, combinée ou non à une brachythérapie, par rapport à une radiothérapie et à un traitement anti-androgénique

    “Radical prostatectomy vs radiation therapy and androgen-suppression therapy in high-risk prostate cancer”

    • Westover, Kenneth;Chen, Ming-Hui;Moul, Judd;Robertson, Cary;Polascik, Thomas;Dosoretz, Daniel;Katin, Michael;Salenius, Sharon;D'Amico, Anthony V.

    Study Type – Therapy (retrospective cohort analysis)Level of Evidence 2bWhat's known on the subject? and What does the study add?Prostate cancer is generally considered to be high risk when the prostate-specific antigen (PSA) concentration is >20 ng/mL, the Gleason score is ≥8 or the American Joint Commission on Cancer (AJCC) tumour (T) category is ≥2c. There is no consensus on the best treatment for men with prostate cancer that includes these high-risk features. Options include external beam radiation therapy (EBRT) with androgen suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined-modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant RT in cases where there are unfavourable pathological features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion. While outcomes for both approaches have been published independently these treatments have not been compared in the setting of ...


Mots clés : Prostate; Traitements (Traitements localisés : applications cliniques)

Mené entre 2009 et 2011 sur 115 patients atteints d'un cancer résécable de l'œsophage ou de la jonction gastro-œsophagienne (âge : 18 à 75 ans), cet essai multicentrique international évalue, du point de vue de la morbidité, l'intérêt d'une œsophagectomie mini-invasive par rapport à une œsophagectomie par voie ouverte

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    Mené entre 2009 et 2011 sur 115 patients atteints d'un cancer résécable de l'œsophage ou de la jonction gastro-œsophagienne (âge : 18 à 75 ans), cet essai multicentrique international évalue, du point de vue de la morbidité, l'intérêt d'une œsophagectomie mini-invasive par rapport à une œsophagectomie par voie ouverte

    “Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial”

    • Biere, Surya S. A. Y.;van Berge Henegouwen, Mark I.;Maas, Kirsten W.;Bonavina, Luigi;Rosman, Camiel;Garcia, Josep Roig;Gisbertz, Suzanne S.;Klinkenbijl, Jean H. G.;Hollmann, Markus W.;de Lange, Elly S. M.;Bonjer, H. Jaap;van der Peet, Donald L.;Cuesta, Miguel A.

    Surgical resection is regarded as the only curative option for resectable oesophageal cancer, but pulmonary complications occurring in more than half of patients after open oesophagectomy are a great concern. We assessed whether minimally invasive oesophagectomy reduces morbidity compared with open oesophagectomy. We did a multicentre, open-label, randomised controlled trial at five study centres in three countries between June 1, 2009, and March 31, 2011. Patients aged 18?75 years with resectable cancer of the oesophagus or gastro-oesophageal junction were randomly assigned via a computer-generated randomisation sequence to receive either open transthoracic or minimally invasive transthoracic oesophagectomy. Randomisation was stratified by centre. Patients, and investigators undertaking interventions, assessing outcomes, and analysing data, were not masked to group assignment. The primary outcome was pulmonary infection within the first 2 weeks after surgery and during the whole stay ...


  • Is minimally invasive preferable to open oesophagectomy?
    The Lancet, sous presse, 2012 (commentaire)
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    Mené entre 2009 et 2011 sur 115 patients atteints d'un cancer résécable de l'œsophage ou de la jonction gastro-œsophagienne (âge : 18 à 75 ans), cet essai multicentrique international évalue, du point de vue de la morbidité, l'intérêt d'une œsophagectomie mini-invasive par rapport à une œsophagectomie par voie ouverte

    “Is minimally invasive preferable to open oesophagectomy?”

    • Law, Simon


Mots clés : Oesophage; Traitements (Traitements localisés : applications cliniques)

A partir de données cliniques portant sur 59 patients âgés de 18 ans ou plus et atteints d'un syndrome de Richter, cette étude rétrospective évalue l'intérêt d'une autogreffe ou d'une greffe allogénique de cellules souches pour améliorer la survie des patients

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    A partir de données cliniques portant sur 59 patients âgés de 18 ans ou plus et atteints d'un syndrome de Richter, cette étude rétrospective évalue l'intérêt d'une autogreffe ou d'une greffe allogénique de cellules souches pour améliorer la survie des patients

    “Autologous and Allogeneic Stem-Cell Transplantation for Transformed Chronic Lymphocytic Leukemia (Richter's Syndrome): A Retrospective Analysis From the Chronic Lymphocytic Leukemia Subcommittee of the Chronic Leukemia Working Party and Lymphoma Working P”

    • Cwynarski, Kate;van Biezen, Anja;de Wreede, Liesbeth;Stilgenbauer, Stephan;Bunjes, Donald;Metzner, Bernd;Koza, Vladimir;Mohty, Mohamad;Remes, Kari;Russell, Nigel;Nagler, Arnon;Scholten, Marijke;de Witte, Theo;Sureda, Anna;Dreger, Peter

    Purpose Patients with Richter's syndrome (RS) have a poor prognosis with conventional chemotherapy. The aim of this study was to evaluate the outcome after autologous stem-cell transplantation (autoSCT) or allogeneic stem-cell transplantation (alloSCT) in RS.Patients and Methods A survey was sent to all European Group for Blood and Marrow Transplantation centers assessing transplantations performed for RS. Eligibility criteria included a diagnosis of RS or secondary lymphoma before SCT, age ≥ 18 years, and SCT performed from 1997 to 2007. Data were analyzed by descriptive statistics and methods from survival analysis.Results Fifty-nine patients were registered. Thirty-four patients had received autoSCT, mostly because of chemotherapy-sensitive disease, and 25 had received alloSCT, with 36% being refractory to chemotherapy at SCT. In 18 allograft recipients (72%), reduced-intensity conditioning (RIC) was used. Three-year estimates of the probabilities of overall survival and ...


Mots clés : Leucémie; Traitements (Traitements localisés : applications cliniques)

Traitements systémiques : découverte et développement

Mené sur un modèle murin de médulloblastome, cette étude évalue l'activité du saridegib, un inihibiteur de la voie de signalisation Hedgehog

  • Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Mené sur un modèle murin de médulloblastome, cette étude évalue l'activité du saridegib, un inihibiteur de la voie de signalisation Hedgehog

    “Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model”

    • Lee, Michelle J.;Hatton, Beryl A.;Villavicencio, Elisabeth H.;Khanna, Paritosh C.;Friedman, Seth D.;Ditzler, Sally;Pullar, Barbara;Robison, Keith;White, Kerry F.;Tunkey, Chris;LeBlanc, Michael;Randolph-Habecker, Julie;Knoblaugh, Sue E.;Hansen, Stacey;Richards, Andrew;Wainwright, Brandon J.;McGovern, Karen;Olson, James M.

    The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely ...


Mots clés : Système nerveux central; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et sur des échantillons tumoraux prélevés sur des patients atteints d'un glioblastome multiforme, cette étude suggère que, par un mécanisme régulant l'expression de la méthyltransférase MGMT, un inhibiteur de STAT3 permettrait de surmonter une résistance au témozolomide

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    Menée in vitro et sur des échantillons tumoraux prélevés sur des patients atteints d'un glioblastome multiforme, cette étude suggère que, par un mécanisme régulant l'expression de la méthyltransférase MGMT, un inhibiteur de STAT3 permettrait de surmonter une résistance au témozolomide

    “STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression”

    • Kohsaka, Shinji;Wang, Lei;Yachi, Kazuhiro;Mahabir, Roshan;Narita, Takuto;Itoh, Tamio;Tanino, Mishie;Kimura, Taichi;Nishihara, Hiroshi;Tanaka, Shinya

    Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA alkylating agent temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to TMZ-induced DNA damage due to elevated expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Here we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of TMZ resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or shRNA downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of IL-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis ...


Mots clés : Système nerveux central; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro, cette étude met en évidence un mécanisme permettant de rendre compte de la synergie observée entre des inhibiteurs de la protéine kinase WEE1 et une chimiothérapie dans des modèles précliniques de cancer du sein

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    Menée in vitro, cette étude met en évidence un mécanisme permettant de rendre compte de la synergie observée entre des inhibiteurs de la protéine kinase WEE1 et une chimiothérapie dans des modèles précliniques de cancer du sein

    “Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1”

    • Aarts, Marieke;Sharpe, Rachel;Garcia-Murillas, Isaac;Gevensleben, Heidrun;Hurd, Melissa S;Shumway, Stuart D;Toniatti, Carlo;Ashworth, Alan;Turner, Nicholas C.

    Inhibition of the protein kinase WEE1 synergises with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterised by dispersed chromosomes and disorganised bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation, combined with high expression of mitotic cyclins and EZH2, predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature CDK1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor ...


Mots clés : Sein; Traitements (Traitements systémiques : découverte et développement)

Menée sur des lignées cellulaires de tumeurs de Wilms et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un inhibiteur du récepteur du facteur de croissance analogue à l'insuline IGFR1

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    Menée sur des lignées cellulaires de tumeurs de Wilms et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un inhibiteur du récepteur du facteur de croissance analogue à l'insuline IGFR1

    “Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition”

    • Bielen, Aleksandra;Box, Gary;Perryman, Lara;Bjerke, Lynn;Popov, Sergey;Jamin, Yann;Jury, Alexa;Valenti, Melanie;Brandon, Alexis de Haven;Martins, Vanessa;Romanet, Vincent;Jeay, Sebastien;Raynaud, Florence I.;Hofmann, Francesco;Robinson, Simon P.;Eccles, Suzanne A.;Jones, Chris

    We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumors. We have now tested whether inhibiting this receptor may be a useful therapeutic strategy by using a panel of Wilms tumor cell lines. Both genetic and pharmacological targeting resulted in inhibition of downstream signaling through PI3 and MAP kinases, G1 cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred synergistic chemosensitisation to doxorubicin and topotecan. In the in vivo setting, s.c. xenografts of WiT49 cells resembled malignant rhabdoid tumors rather than Wilms tumors. Treatment with an IGF1R inhibitor (NVP-AEW541) showed no discernable antitumor activity and no downstream pathway inactivation. By contrast, Wilms tumor cells established orthotopically within the ...


Mots clés : Rein; Traitements (Traitements systémiques : découverte et développement)

Mené sur 16 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase I/II évalue le bortezomib en combinaison avec du carboplatine et du bevacizumab en traitement de première ligne

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    Mené sur 16 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase I/II évalue le bortezomib en combinaison avec du carboplatine et du bevacizumab en traitement de première ligne

    “Phase-I/II Study of Bortezomib in Combination with Carboplatin and Bevacizumab as First-Line Therapy in Patients With Advanced Non-Small-Cell Lung Cancer”

    • Piperdi, Bilal;Walsh, William V.;Bradley, Kendra;Zhou, Zheng;Bathini, Venu;Hanrahan-Boshes, Meredith;Hutchinson, Lloyd;Perez-Soler, Roman

    Background: This study aimed to establish the maximum tolerated dose (MTD) of weekly bortezomib in combination with fixed standard doses of carboplatin and bevacizumab, and to estimate the efficacy (response rate and progression free survival [PFS]) and safety of combination therapy with carboplatin, bortezomib, and bevacizumab as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods: Patients were assigned to three dose levels of weekly bortezomib with the fixed standard doses of carboplatin AUC 6 and bevacizumab (15 mg/kg) every 3 weeks using a standard phase-I design. Bortezomib doses were 1.3 mg/m2, 1.6 mg/m2, and 1.8 mg/m2 weekly on day 1 and day 8 of every 3-week cycle. A maximum of six cycles was administered. Patients with complete, partial response or stable disease were continued on single-agent bevacizumab (15 mg/kg every 3 weeks) as maintenance therapy. In phase II, either level III or MTD was administered to evaluate the efficacy and ...


Mots clés : Poumon; Traitements (Traitements systémiques : découverte et développement)

Mené sur 29 patients atteints d'un myélome multiple récidivant ou réfractaire, cet essai de phase I évalue l'elotuzumab en combinaison avec du lénalidomide et de la dexaméthasone à faible dose

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    Mené sur 29 patients atteints d'un myélome multiple récidivant ou réfractaire, cet essai de phase I évalue l'elotuzumab en combinaison avec du lénalidomide et de la dexaméthasone à faible dose

    “Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma”

    • Lonial, Sagar;Vij, Ravi;Harousseau, Jean-Luc;Facon, Thierry;Moreau, Philippe;Mazumder, Amitabha;Kaufman, Jonathan L.;Leleu, Xavier;Tsao, L. Claire;Westland, Christopher;Singhal, Anil K.;Jagannath, Sundar

    Purpose This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM).Patients and Methods Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression.Results Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent ...


Mots clés : Myélome multiple et maladies immunoprolifératives; Traitements (Traitements systémiques : découverte et développement)

Menée sur des lignées cellulaires et à l'aide d'un modèle murin de carcinome hépatocellulaire, cette étude évalue les effets antitumoraux de deux inhibiteurs de la voie mTOR, seuls ou en combinaison

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    Menée sur des lignées cellulaires et à l'aide d'un modèle murin de carcinome hépatocellulaire, cette étude évalue les effets antitumoraux de deux inhibiteurs de la voie mTOR, seuls ou en combinaison

    “mTOR Inhibitors Synergize Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma”

    • Thomas, Hala Elnakat;Mercer, Carol A.;Carnevalli, Larissa S.;Park, Jongsun;Andersen, Jesper B.;Conner, Elizabeth A.;Tanaka, Kazuhiro;Matsutani, Tomoo;Iwanami, Akio;Aronow, Bruce J.;Manway, Liu;Maira, S. Michel;Thorgeirsson, Snorri S.;Mischel, Paul S.;Thomas, George;Kozma, Sara C.

    Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian Target of Rapamycin (mTOR)-signaling is upregulated in 50% of HCCs, we compared the effects of the FDA-approved mTOR-allosteric inhibitor, RAD001, with a new generation PI3K/mTOR ATP-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled 4E-BP1 dephosphorylation, which is implicated in the suppression of tumor cell proliferation. In a mouse model approximating human HCC, the drugs in combination, but not singly, induced a dramatic regression in tumor burden. However in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggest additional target(s) may also be involved. Microarray analyses revealed a large number of genes that reverted to normal liver tissue ...


Mots clés : Foie; Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par des anticorps monoclonaux dirigés contre un récepteur du facteur de croissance tumorale, 4-1BB, pour l'immunothérapie des cancers, notamment des mélanomes, carcinomes rénaux et cancers ovariens

  • Immunotherapy of Cancer with 4-1BB
    Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par des anticorps monoclonaux dirigés contre un récepteur du facteur de croissance tumorale, 4-1BB, pour l'immunothérapie des cancers, notamment des mélanomes, carcinomes rénaux et cancers ovariens

    “Immunotherapy of Cancer with 4-1BB”

    • Vinay, Dass S.;Kwon, Byoung S.

    4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces cytokine production, and prevents activation-induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8+ T-cell activating, IFN-γ producing, and cytolytic marker–inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB–activated CD8+ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Mené sur 110 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue un composé appelé RO4929097, un inhibiteur d'une enzyme, la gamma secrétase, impliquée dans la voie de signalisation Notch

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    Mené sur 110 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue un composé appelé RO4929097, un inhibiteur d'une enzyme, la gamma secrétase, impliquée dans la voie de signalisation Notch

    “Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors”

    • Tolcher, Anthony W.;Messersmith, Wells A.;Mikulski, Stanislaw M.;Papadopoulos, Kyriakos P.;Kwak, Eunice L.;Gibbon, Darlene G.;Patnaik, Amita;Falchook, Gerald S.;Dasari, Arvind;Shapiro, Geoffrey I.;Boylan, John F.;Xu, Zhi-Xin;Wang, Ka;Koehler, Astrid;Song, James;Middleton, Steven A.;Deutsch, Jonathan;DeMario, Mark;Kurzrock, Razelle;Wheler, Jennifer J.

    Purpose To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies.Patients and Methods Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects.Results Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par des inhibiteurs de la voie de signalisation du mévalonate pour le traitement des cancers

  • Novel aspects of mevalonate pathway inhibitors as antitumor agents
    Clinical Cancer Research, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par des inhibiteurs de la voie de signalisation du mévalonate pour le traitement des cancers

    “Novel aspects of mevalonate pathway inhibitors as antitumor agents”

    • Thurnher, Martin;Nussbaumer, Oliver;Gruenbacher, Georg

    The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as the statins and bisphosphonates, inhibit mevalonate metabolism and have therefore also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. First evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Drug-induced inhibition of protein prenylation may induce sequential cellular stress responses including the unfolded protein response and autophagy, which eventually translate into ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les travaux récents suggérant l'intérêt de cibler le compartiment tumoral hypoxique pour améliorer l'efficacité d'un traitement anti-angiogénique

  • Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia
    Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents suggérant l'intérêt de cibler le compartiment tumoral hypoxique pour améliorer l'efficacité d'un traitement anti-angiogénique

    “Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia”

    • Rapisarda, Annamaria;Melillo, Giovanni

    Cancer cells rely on angiogenesis to fulfil their need for oxygen and nutrients; hence, agents targeting angiogenic pathways and mediators have been investigated as potential cancer drugs. Although this strategy has demonstrated delayed tumour progression—leading to progression-free survival and overall survival benefits compared with standard therapy—in some patients, the results are more modest than predicted. A significant number of patients either do not respond to antiangiogenic agents or fairly rapidly develop resistance to them, which raises questions about how resistance develops and how it can be overcome. Furthermore, whether cancers, once they develop resistance, become more invasive or lead to metastatic disease remains unclear. Several mechanisms of resistance have been recently proposed and emerging evidence indicates that, under certain experimental conditions, antiangiogenic agents increase intratumour hypoxia by promoting vessel pruning and inhibiting ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par des molécules ciblant des anomalies épigénétiques pour le traitement des cancers

  • Emerging Epigenetic Targets and Therapies in Cancer Medicine
    Cancer Discovery, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par des molécules ciblant des anomalies épigénétiques pour le traitement des cancers

    “Emerging Epigenetic Targets and Therapies in Cancer Medicine”

    • Popovic, Relja;Licht, Jonathan D.

    Abnormalities in the epigenetic regulation of chromatin structure and function can lead to aberrant gene expression and cancer development. Consequently, epigenetic therapies aim to restore normal chromatin modification patterns through the inhibition of various components of the epigenetic machinery. Histone deacetylase and DNA methyltransferase inhibitors represent the first putative epigenetic therapies; however, these agents have pleiotropic effects and it remains unclear how they lead to therapeutic responses. More recently, drugs that inhibit histone methyltransferases were developed, perhaps representing more specific agents. We review emerging epigenetic targets in cancer and present recent models of promising epigenetic therapies.Significance: The use of DNA methyltransferase and histone deacetylase inhibitors in patients has validated the use of drugs targeted to epigenetic enzymes and strengthened the need for development of additional therapies. In this review, we ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par l'usage de statines, en combinaison avec une chimiothérapie, pour améliorer l'efficacité des traitements de plusieurs types de tumeurs

  • Statins and cancer: Current and future prospects
    Cancer Letters, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par l'usage de statines, en combinaison avec une chimiothérapie, pour améliorer l'efficacité des traitements de plusieurs types de tumeurs

    “Statins and cancer: Current and future prospects”

    • Osmak, Maja

    Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase. They exhibit effects beyond cholesterol reduction, including anticancer activity. This review presents the effects of statins in vitro and their possible molecular anticancer mechanisms and critically discusses the data regarding the role of statins in cancer prevention. Finally, this review focuses on the use of statins combined with other chemotherapeutics to increase the effectiveness of cancer treatments. Despite rare and inconclusive clinical data, the preclinical results strongly suggest that such combined treatment could be a promising new strategy for the treatment of certain tumor types.


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par la combinaison d'agents anti-angiogéniques, reposant sur différents mécanismes d'action, pour combattre l'apparition d'une résistance thérapeutique dans les cancers métastasés

  • Combining Antiangiogenics to Overcome Resistance: rationale and clinical experience
    Clinical Cancer Research, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par la combinaison d'agents anti-angiogéniques, reposant sur différents mécanismes d'action, pour combattre l'apparition d'une résistance thérapeutique dans les cancers métastasés

    “Combining Antiangiogenics to Overcome Resistance: rationale and clinical experience”

    • Moreno Garcia, Victor;Basu, Bristi;Molife, Lulama R;Kaye, Stan B

    Antiangiogenic therapies are now well established in oncology clinical practice, however, despite initial optimism results of late phase trials, especially in the adjuvant setting, have largely proven disappointing to date. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is by combining antiangiogenic agents with different mechanisms of action. Early phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those which target the VEGF pathway, angiopoietins, as well as vascular disrupting agents are increasing in number. A promising example of this combination strategy is the combination of sorafenib and bevacizumab in different tumor types such as ovarian carcinoma or glioblastoma. However, overlapping and cumulative toxicity pose a real ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Menée sur des lignées cellulaires de cancer du rein et de la prostate, cette étude montre que, en restaurant l'expression de PTEN, divers inhibiteurs d'éléments de la voie de signalisation Akt/mTOR permettent de surmonter une résistance au sunitinib

  • Modulation of Akt/mTOR Signaling Overcomes Sunitinib Resistance in Renal and Prostate Cancer Cells
    Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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    Menée sur des lignées cellulaires de cancer du rein et de la prostate, cette étude montre que, en restaurant l'expression de PTEN, divers inhibiteurs d'éléments de la voie de signalisation Akt/mTOR permettent de surmonter une résistance au sunitinib

    “Modulation of Akt/mTOR Signaling Overcomes Sunitinib Resistance in Renal and Prostate Cancer Cells”

    • Makhov, Peter;Golovine, Konstantin;Kutikov, Alexander;Teper, Ervin;Canter, Daniel J;Simhan, Jay;Uzzo, Robert G.;Kolenko, Vladimir M

    Tyrosine kinase inhibitors (TKIs) exhibit impressive activity against advanced renal cell carcinoma. However, recent clinical studies have demonstrated an equivocal response to sunitinib in patients with castration-resistant prostate cancer. The tumor suppressor phosphatase and tensin homolog (PTEN) acts as a gatekeeper of the PI3K/Akt/mTOR cell-survival pathway. Our experiments demonstrate that PTEN expression inversely correlates with sunitinib resistance in renal and prostate cancer cells. Restoration of PTEN expression markedly increases sensitivity of tumor cells to sunitinib both in vitro and in vivo. In addition, pharmacologic manipulation of PI3K/Akt/mTOR signaling with PI3K/mTOR inhibitor, GDC-0980, mTOR inhibitor, temsirolimus, or pan-Akt inhibitor, GSK690693, was able to overcome sunitinib resistance in cancer cells. Our findings underscore the importance of PTEN expression in relation to sunitinib resistance and imply a direct cytotoxic effect by sunitinib on tumor cells ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Mené sur 103 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue un composé appelé MK-0752, un inhibiteur d'une enzyme, la gamma secrétase, impliquée dans l'activation de la voie de signalisation Notch

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    Mené sur 103 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue un composé appelé MK-0752, un inhibiteur d'une enzyme, la gamma secrétase, impliquée dans l'activation de la voie de signalisation Notch

    “Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors”

    • Krop, Ian;Demuth, Tim;Guthrie, Tina;Wen, Patrick Y.;Mason, Warren P.;Chinnaiyan, Prakash;Butowski, Nicholas;Groves, Morris D.;Kesari, Santosh;Freedman, Steven J.;Blackman, Samuel;Watters, James;Loboda, Andrey;Podtelezhnikov, Alexei;Lunceford, Jared;Chen, Cong;Giannotti, Maxine;Hing, Jeremy;Beckman, Robert;LoRusso, Patricia

    Purpose Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752.Patients and Methods MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition.Results Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Mené sur 116 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue le saracatinib, un inhibiteur sélectif de la kinase Src, en combinaison avec du carboplatine ou du paclitaxel

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    Mené sur 116 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue le saracatinib, un inhibiteur sélectif de la kinase Src, en combinaison avec du carboplatine ou du paclitaxel

    “Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours”

    • Kaye, S.;Aamdal, S.;Jones, R.;Freyer, G.;Pujade-Lauraine, E.;de Vries, E. G. E.;Barriuso, J.;Sandhu, S.;Tan, D. S. W.;Hartog, V.;Kuenen, B.;Ruijter, R.;Kristensen, G. B.;Nyakas, M.;Barrett, S.;Burke, W.;Pietersma, D.;Stuart, M.;Emeribe, U.;Boven, E.

    Background: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. Methods: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m−2 q3w, paclitaxel 80 mg m−2 every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m−2 q3w. The primary endpoint was safety/tolerability. Results: A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade greater than or equal to3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; greater than ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Traitements systémiques : applications cliniques

A partir d'une revue de la littérature, cette méta-analyse (20 essais, 6 712 patients) évalue l'efficacité du traitement adjuvant d'un cancer des voies biliaires

  • Adjuvant Therapy in the Treatment of Biliary Tract Cancer: A Systematic Review and Meta-Analysis
    Journal of Clinical Oncology, sous presse, 2012 (résumé)
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    A partir d'une revue de la littérature, cette méta-analyse (20 essais, 6 712 patients) évalue l'efficacité du traitement adjuvant d'un cancer des voies biliaires

    “Adjuvant Therapy in the Treatment of Biliary Tract Cancer: A Systematic Review and Meta-Analysis”

    • Horgan, Anne M.;Amir, Eitan;Walter, Thomas;Knox, Jennifer J.

    Purpose The benefit of adjuvant therapy (AT) for biliary tract cancer (BTC) is unclear, with conflicting results from nonrandomized studies. We report a systematic review and meta-analysis to determine the impact of AT on survival.Methods Studies published between 1960 and November 2010, which evaluated adjuvant chemotherapy (CT), radiotherapy (RT), or both (CRT) compared with curative-intent surgery alone for resected BTC were included. Only tumors of the gallbladder and bile ducts were assessed. Published data were extracted and computed into odds ratios (ORs) for death at 5 years. Subgroup analyses of benefit based on lymph node (LN) or resection margin positivity (R1) were prespecified. Data were weighted by generic inverse variance and pooled using random-effect modeling.Results Twenty studies involving 6,712 patients were analyzed. There was a nonsignificant improvement in overall survival with any AT compared with surgery alone (pooled OR, 0.74; P = .06). There was no ...


Mots clés : Voies biliaires; Traitements (Traitements systémiques : applications cliniques)

Cet article analyse les résultats contradictoires d'études sur l'association entre des polymorphismes de CYP2D6 et la réponse au tamoxifène chez les patientes atteintes d'un cancer du sein

  • Tamoxifen and CYP2D6: A Contradiction of Data
    The Oncologist, sous presse, 2012 (résumé)
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    Cet article analyse les résultats contradictoires d'études sur l'association entre des polymorphismes de CYP2D6 et la réponse au tamoxifène chez les patientes atteintes d'un cancer du sein

    “Tamoxifen and CYP2D6: A Contradiction of Data”

    • Hertz, Daniel L.;McLeod, Howard L.;Irvin, William J.

    Abstract Tamoxifen is an effective antiestrogen used in the treatment of hormone receptor–positive breast cancer. Bioconversion of tamoxifen to endoxifen, its most abundant active metabolite, is primarily dependent on the activity of cytochrome P450 2D6 (CYP2D6), which is highly polymorphic. Over 20 published studies have reported on the potential association between CYP2D6 polymorphism and tamoxifen treatment outcome, with highly inconsistent results. The purpose of this review is to explore differences among 17 independent studies to identify factors that may have contributed to the discrepant findings. This report discusses six putative factors that are grouped into two categories: (a) clinical management criteria: hormone receptor classification, menopausal status, and tamoxifen combination therapy; (b) pharmacologic criteria: genotyping comprehensiveness, CYP2D6 inhibitor coadministration, and tamoxifen adherence. Comparison of these factors between the positive and negative ...


Mots clés : Sein; Traitements (Traitements systémiques : applications cliniques)

A partir d'une revue systématique de la littérature, cette étude évalue l'efficacité et la toxicité du trastuzumab en traitement adjuvant d'un cancer du sein chez les patientes âgées de plus de 60 ans

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    A partir d'une revue systématique de la littérature, cette étude évalue l'efficacité et la toxicité du trastuzumab en traitement adjuvant d'un cancer du sein chez les patientes âgées de plus de 60 ans

    “Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: A systematic review of randomized controlled trials”

    • Brollo, Janaina;Curigliano, Giuseppe;Disalvatore, Davide;Marrone, Bianca Fontana;Criscitiello, Carmen;Bagnardi, Vincenzo;Kneubil, Maximiliano Cassilha;Fumagalli, Luca;Locatelli, Marzia;Manunta, Silvia;Goldhirsch, Aron

    Trastuzumab, in combination with chemotherapy, is the gold standard in the adjuvant treatment of patients with HER2 positive breast cancer. Limited data are available on the role of adjuvant trastuzumab in the elderly population. We performed a systematic review of prospective randomized trials with available data on the use of adjuvant trastuzumab in patients older than 60years, focusing on both the efficacy and the cardiac safety. Data extrapolated from two prospective trials were included for efficacy and cardiac safety. A significant 47% relative risk reduction was observed in elderly patients receiving trastuzumab compared to chemotherapy alone (pooled Hazard Ratio: 0.53; 95% CI, 0.36–0.77). The pooled proportion of cardiac events in elderly patients treated with trastuzumab was 5% (95% CI, 4–7%). The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER-2 positive breast cancer. Acute and chronic medical ...


Mots clés : Sein; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur le traitement du cancer de la prostate résistant à la castration

  • Clinical development of novel therapeutics for castration-resistant prostate cancer
    CA: A Cancer Journal for Clinicians, sous presse, 2012 (article en libre accès)
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    Cet article passe en revue les travaux récents sur le traitement du cancer de la prostate résistant à la castration

    “Clinical development of novel therapeutics for castration-resistant prostate cancer”

    • Galsky, Matthew D.;Small, Alexander C.;Tsao, Che-kai;Oh, William K.

    There have been more drugs approved by the US Food and Drug Administration for the treatment of castration-resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration-resistant prostate cancer has undeniably accelerated the transition of novel approaches from “bench to bedside,” the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration-resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration-resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease. CA Cancer J Clin 2012;. © ...


Mots clés : Prostate; Traitements (Traitements systémiques : applications cliniques)

Ces trois essais (2 "phase II et 1 "phase III") évaluent l'ipilimumab, l'erlotinib et le nab-paclitaxel pour le traitement des patients atteints d'un cancer avancé du poumon non à petites cellules

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    Ces trois essais (2 "phase II et 1 "phase III") évaluent l'ipilimumab, l'erlotinib et le nab-paclitaxel pour le traitement des patients atteints d'un cancer avancé du poumon non à petites cellules

    “Weekly nab-Paclitaxel in Combination With Carboplatin Versus Solvent-Based Paclitaxel Plus Carboplatin as First-Line Therapy in Patients With Advanced Non–Small-Cell Lung Cancer: Final Results of a Phase III Trial”

    • Socinski, Mark A.;Bondarenko, Igor;Karaseva, Nina A.;Makhson, Anatoly M.;Vynnychenko, Igor;Okamoto, Isamu;Hon, Jeremy K.;Hirsh, Vera;Bhar, Paul;Zhang, Hui;Iglesias, Jose L.;Renschler, Markus F.

    Purpose This phase III trial compared the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus carboplatin in advanced non–small-cell lung cancer (NSCLC).Patients and Methods In all, 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 mg/m2 nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 once every 3 weeks (nab-PC) or 200 mg/m2 sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks (sb-PC). The primary end point was objective overall response rate (ORR).Results On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-PC (33% v 25%; response rate ratio, 1.313; 95% CI, 1.082 to 1.593; P = .005) and in patients with squamous histology (41% v 24%; response rate ratio, 1.680; 95% CI, 1.271 to 2.221; P < .001). nab-PC was as effective as sb-PC in patients with nonsquamous histology (ORR, ...


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    Ces trois essais (2 "phase II et 1 "phase III") évaluent l'ipilimumab, l'erlotinib et le nab-paclitaxel pour le traitement des patients atteints d'un cancer avancé du poumon non à petites cellules

    “Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study”

    • Lynch, Thomas J. ; Bondarenko, Igor ; Luft, Alexander ; Serwatowski, Piotr ; Barlesi, Fabrice ; Chacko, Raju ; Sebastian, Martin ; Neal, Joel ; Lu, Haolan ; Cuillerot, Jean-Marie ; Reck, Martin

    Purpose Ipilimumab, which is an anti–cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin.Patients and Methods Patients (N = 204) with chemotherapy-naive non–small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m2) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or ...


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    Ces trois essais (2 "phase II et 1 "phase III") évaluent l'ipilimumab, l'erlotinib et le nab-paclitaxel pour le traitement des patients atteints d'un cancer avancé du poumon non à petites cellules

    “Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial”

    • Jänne, Pasi A. ; Wang, Xiaofei ; Socinski, Mark A. ; Crawford, Jeffrey ; Stinchcombe, Thomas E. ; Gu, Lin ; Capelletti, Marzia ; Edelman, Martin J. ; Villalona-Calero, Miguel A. ; Kratzke, Robert ; Vokes, Everett E. ; Miller, Vincent A.

    Purpose Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics.Patients and Methods Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory.Results PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in ...


  • Method to our Madness or Madness in our Methods? Pitfalls in Trial Methodology
    Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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    Ces trois essais (2 "phase II et 1 "phase III") évaluent l'ipilimumab, l'erlotinib et le nab-paclitaxel pour le traitement des patients atteints d'un cancer avancé du poumon non à petites cellules

    “Method to our Madness or Madness in our Methods? Pitfalls in Trial Methodology”

    • Levine, Mark N. ; Juergens, Rosalyn


Mots clés : Poumon; Traitements (Traitements systémiques : applications cliniques)

A partir de données portant sur un total de 2 605 patients atteints d'un cancer avancé du poumon non à petites cellules (âge moyen : 74 ans), cette méta-analyse évalue l'efficacité et la toxicité d'une chimiothérapie à base de doublets par comparaison avec une monothérapie

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    A partir de données portant sur un total de 2 605 patients atteints d'un cancer avancé du poumon non à petites cellules (âge moyen : 74 ans), cette méta-analyse évalue l'efficacité et la toxicité d'une chimiothérapie à base de doublets par comparaison avec une monothérapie

    “Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: A meta-analysis”

    • Des Guetz, Gaetan;Uzzan, Bernard;Nicolas, Patrick;Valeyre, Dominique;Sebbane, Georges;Morere, Jean-François

    Background In patients with advanced non-small cell lung cancer (NSCLC) aged more than 70 years, the benefit-to-risk ratio of doublet chemotherapy vs single-agent is not established. Methods We performed a meta-analysis (MA), with a PubMed query using keywords simultaneously (Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non-small cell lung/drug therapy). Abstracts from ASCO, WCLC, and ESMO proceedings were reviewed. Articles were also obtained by cross-checking references. Third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination with or without platinum were included. The efficacy outcomes were Overall Response Rate (ORR) and 1-Year Overall Survival (OS). We used EasyMA software and a random-effect model in case of heterogeneity. Results This MA comprised 10 studies including 2605 patients (mean age 74; 1866 men and 620 women; 654 stage IIIB and 1677 stage IV; 839 squamous cell cancers, ...


Mots clés : Poumon; Traitements (Traitements systémiques : applications cliniques)

A partir de données d'un registre canadien des cancers portant sur 6 304 patients ayant subi une résection chirurgicale pour un cancer du poumon non à petites cellules entre 2001 et 2006, cette étude analyse l'évolution du recours à une chimiothérapie adjuvante chez les patients âgés et analyse la survie des patients par tranche d'âge (70-74, 75-79 et supérieur à 80 ans)

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    A partir de données d'un registre canadien des cancers portant sur 6 304 patients ayant subi une résection chirurgicale pour un cancer du poumon non à petites cellules entre 2001 et 2006, cette étude analyse l'évolution du recours à une chimiothérapie adjuvante chez les patients âgés et analyse la survie des patients par tranche d'âge (70-74, 75-79 et supérieur à 80 ans)

    “Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer in the Elderly: A Population-Based Study in Ontario, Canada”

    • Cuffe, Sinead;Booth, Christopher M.;Peng, Yingwei;Darling, Gail E.;Li, Gavin;Kong, Weidong;Mackillop, William J.;Shepherd, Frances A.

    Purpose Non–small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant chemotherapy. However, the elderly were under-represented in these studies, raising concerns regarding the reproducibility of the study results in clinical practice.Patients and Methods By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and ≥ 80 years. As a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to 2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks ...


Mots clés : Poumon; Traitements (Traitements systémiques : applications cliniques)

Mené sur 484 patientes atteintes d'un cancer ovarien récidivant ou d'un cancer primitif du péritoine ou d'un cancer de la trompe de Fallope, cet essai de phase III évalue, du point de vue de la survie sans progression, l’ajout de bevacizumab à une chimiothérapie combinant gemcitabine et carboplatine

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    Mené sur 484 patientes atteintes d'un cancer ovarien récidivant ou d'un cancer primitif du péritoine ou d'un cancer de la trompe de Fallope, cet essai de phase III évalue, du point de vue de la survie sans progression, l’ajout de bevacizumab à une chimiothérapie combinant gemcitabine et carboplatine

    “OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer”

    • Aghajanian, Carol;Blank, Stephanie V.;Goff, Barbara A.;Judson, Patricia L.;Teneriello, Michael G.;Husain, Amreen;Sovak, Mika A.;Yi, Jing;Nycum, Lawrence R.

    Purpose This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC).Patients and Methods Patients with platinum-sensitive ROC (recurrence ≥ 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety.Results Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective ...


Mots clés : Ovaire; Traitements (Traitements systémiques : applications cliniques)

Mené sur 129 patients atteints d'un lymphome hodgkinien récidivant ou réfractaire à une greffe autologue de cellules souches, cet essai de phase II évalue, du point de vue du taux de réponse objective, le panobinostat

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    Mené sur 129 patients atteints d'un lymphome hodgkinien récidivant ou réfractaire à une greffe autologue de cellules souches, cet essai de phase II évalue, du point de vue du taux de réponse objective, le panobinostat

    “Panobinostat in Patients With Relapsed/Refractory Hodgkin's Lymphoma After Autologous Stem-Cell Transplantation: Results of a Phase II Study”

    • Younes, Anas;Sureda, Anna;Ben-Yehuda, Dina;Zinzani, Pier Luigi;Ong, Tee-Chuan;Prince, H. Miles;Harrison, Simon J.;Kirschbaum, Mark;Johnston, Patrick;Gallagher, Jennifer;Le Corre, Christophe;Shen, Angela;Engert, Andreas

    Purpose Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population.Patients and Methods Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed.Results The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 patients ...


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    Mené sur 129 patients atteints d'un lymphome hodgkinien récidivant ou réfractaire à une greffe autologue de cellules souches, cet essai de phase II évalue, du point de vue du taux de réponse objective, le panobinostat

    “Brentuximab Vedotin and Panobinostat: New Drugs for Hodgkin's Lymphoma—Can They Make One of Medical Oncology's Chemotherapy Success Stories More Successful?”

    • Canellos, George P.


Mots clés : Lymphome; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur les stratégies personnalisées pour le traitement adjuvant d'une tumeur stromale gastro-intestinale

  • Adjuvant treatment of GIST: patient selection and treatment strategies
    Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur les stratégies personnalisées pour le traitement adjuvant d'une tumeur stromale gastro-intestinale

    “Adjuvant treatment of GIST: patient selection and treatment strategies”

    • Joensuu, Heikki

    Tyrosine kinase inhibitors that target the key molecular drivers of gastrointestinal stromal tumour (GIST) are effective treatments of advanced-stage GIST. Yet, most of these patients succumb to the disease. Approximately 60% of patients with GIST are cured by surgery, and these individuals can be identified by risk stratification schemes based on tumour size, mitosis count and site, and assessment of rupture. Two large randomized trials have evaluated imatinib as adjuvant treatment for operable, KIT-positive GIST; adjuvant imatinib substantially improved time to recurrence. One of these trials reported that 3 years of adjuvant imatinib improves overall survival of patients who have a high estimated risk for recurrence of GIST compared with 1 year of imatinib. The optimal adjuvant strategy remains unknown and some patients might benefit from longer than 3 years of imatinib treatment. However, a strategy that involves GIST risk assessment following surgery using a validated scheme, ...


Mots clés : Appareil digestif (autre); Traitements (Traitements systémiques : applications cliniques)

Cet article analyse et compare les différents usages de traitements adjuvants pour cinq principaux types de tumeurs solides

  • Comparative clinical benefits of systemic adjuvant therapy for paradigm solid tumors
    Cancer treatment reviews, sous presse, 2012 (résumé)
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    Cet article analyse et compare les différents usages de traitements adjuvants pour cinq principaux types de tumeurs solides

    “Comparative clinical benefits of systemic adjuvant therapy for paradigm solid tumors”

    • Kirkwood, John M.;Tarhini, Ahmad;Sparano, Joseph A.;Patel, Prapti;Schiller, Joan H.;Vergo, Maxwell T.;Benson Iii, Al B.;Tawbi, Hussein

    Adjuvant therapy employing cytotoxic chemotherapy, molecularly targeted agents, immunologic, and hormonal agents has shown a significant impact upon a variety of solid tumors. The principles that guide adjuvant therapy differ among various tumor types and specific modalities, but generally indicate a greater impact of therapy in the postsurgical setting of micrometastatic disease, for which adjuvant therapy is commonly pursued, vs. the setting of gross unresectable disease. This review of adjuvant therapies in current use for five major solid tumors highlights the rationale for current effective adjuvant therapy, and draws comparisons between the adjuvant regimens that have found application in solid tumors.


Mots clés : Cancer (général); Traitements (Traitements systémiques : applications cliniques)

Cet article présente les recommandations d'un groupe international d'experts sur la prise en charge de l'ototoxicité associée à une chimiothérapie à base de sels de platine chez les patients pédiatriques

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    Cet article présente les recommandations d'un groupe international d'experts sur la prise en charge de l'ototoxicité associée à une chimiothérapie à base de sels de platine chez les patients pédiatriques

    “Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale”

    • Brock, Penelope R.;Knight, Kristin R.;Freyer, David R.;Campbell, Kathleen C.M.;Steyger, Peter S.;Blakley, Brian W.;Rassekh, Shahrad R.;Chang, Kay W.;Fligor, Brian J.;Rajput, Kaukab;Sullivan, Michael;Neuwelt, Edward A.

    Purpose The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important.Patients and Methods This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection.Results Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally ...


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    Cet article présente les recommandations d'un groupe international d'experts sur la prise en charge de l'ototoxicité associée à une chimiothérapie à base de sels de platine chez les patients pédiatriques

    “New International Society of Pediatric Oncology Boston Ototoxicity Grading Scale for Pediatric Oncology: Still Room for Improvement”

    • Gurney, James G. ; Bass, Johnnie K.


Mots clés : Cancer (général); Traitements (Traitements systémiques : applications cliniques)

Combinaison de traitements localisés et systémiques

Mené sur 168 patients atteints d'un cancer de la prostate présentant un risque élevé de récidive (durée médiane de suivi : 70 mois), cet essai randomisé de phase III compare, du point de vue de la récidive biochimique, locale ou distante, l'efficacité à long terme et les facteurs clinicopathologiques d'échec d'une radiothérapie conventionnelle fractionnée et d'une radiothérapie hypofractionnée combinée à un traitement anti-androgénique

  • Updated Results and Patterns of Failure in a Randomized Hypofractionation Trial for High-risk Prostate Cancer
    International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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    Mené sur 168 patients atteints d'un cancer de la prostate présentant un risque élevé de récidive (durée médiane de suivi : 70 mois), cet essai randomisé de phase III compare, du point de vue de la récidive biochimique, locale ou distante, l'efficacité à long terme et les facteurs clinicopathologiques d'échec d'une radiothérapie conventionnelle fractionnée et d'une radiothérapie hypofractionnée combinée à un traitement anti-androgénique

    “Updated Results and Patterns of Failure in a Randomized Hypofractionation Trial for High-risk Prostate Cancer”

    • Arcangeli, Stefano;Strigari, Lidia;Gomellini, Sara;Saracino, Biancamaria;Petrongari, Maria Grazia;Pinnarò, Paola;Pinzi, Valentina;Arcangeli, Giorgio

    To report long-term results and patterns of failure after conventional and hypofractionated radiation therapy in high-risk prostate cancer. This randomized phase III trial compared conventional fractionation (80 Gy at 2 Gy per fraction in 8 weeks) vs hypofractionation (62 Gy at 3.1 Gy per fraction in 5 weeks) in combination with 9-month androgen deprivation therapy in 168 patients with high-risk prostate cancer. Freedom from biochemical failure (FFBF), freedom from local failure (FFLF), and freedom from distant failure (FFDF) were analyzed. In a median follow-up of 70 months, biochemical failure (BF) occurred in 35 of the 168 patients (21%) in the study. Among these 35 patients, local failure (LF) only was detected in 11 (31%), distant failure (DF) only in 16 (46%), and both LF and DF in 6 (17%). In 2 patients (6%) BF has not yet been clinically detected. The risk reduction by hypofractionation was significant in BF (10.3%) but not in LF and DF. We found that hypofractionation, with ...


Mots clés : Prostate; Traitements (Combinaison de traitements localisés et systémiques)

Cet article fait le point sur l'efficacité et la toxicité de nouveaux protocoles de chimioradiothérapie pour traiter un cancer du poumon non à petites cellules de stade III-A ou III-B

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    Cet article fait le point sur l'efficacité et la toxicité de nouveaux protocoles de chimioradiothérapie pour traiter un cancer du poumon non à petites cellules de stade III-A ou III-B

    “Novel Approaches of Chemoradiotherapy in Unresectable Stage IIIA and Stage IIIB Non-Small Cell Lung Cancer”

    • Stinchcombe, Thomas E.;Bogart, Jeffrey A.

    Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease, and appropriate patients are candidates for chemoradiotherapy with curative intent. The optimal treatment paradigm is currently undefined. Concurrent chemoradiotherapy, compared with sequential chemotherapy and thoracic radiation therapy (TRT), results in superior overall survival outcomes as a result of better locoregional control. Recent trials have revealed efficacy for newer chemotherapy combinations similar to that of older chemotherapy combinations with concurrent TRT and a lower rate of some toxicities. Ongoing phase III trials will determine the roles of cisplatin and pemetrexed concurrent with TRT in patients with nonsquamous histology, cetuximab, and the L-BLP25 vaccine. It is unlikely that bevacizumab will have a role in stage III disease because of its toxicity. Erlotinib, gefitinib, and crizotinib have not been evaluated in stage III patients selected ...


Mots clés : Poumon; Traitements (Combinaison de traitements localisés et systémiques)

Mené sur 69 patients atteints d'un cancer rectal localement avancé (durée médiane de suivi : 69 mois), cet essai multi-institutionnel de phase II évalue, du point de vue de la survie globale, l'efficacité et la toxicité d'une radiothérapie pelvienne pré-opératoire combinée à une dose concomitante de rayonnement additionnel du lit tumoral et à une chimiothérapie par 5-fluorouracile / leucovorine

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    Mené sur 69 patients atteints d'un cancer rectal localement avancé (durée médiane de suivi : 69 mois), cet essai multi-institutionnel de phase II évalue, du point de vue de la survie globale, l'efficacité et la toxicité d'une radiothérapie pelvienne pré-opératoire combinée à une dose concomitante de rayonnement additionnel du lit tumoral et à une chimiothérapie par 5-fluorouracile / leucovorine

    “Long-Term Follow-Up of Preoperative Pelvic Radiation Therapy and Concomitant Boost Irradiation in Locally Advanced Rectal Cancer Patients: A Multi-Institutional Phase II Study (KROG 04-01)”

    • Lee, Jong Hoon;Kim, Dae Yong;Nam, Taek-Keun;Yoon, Sei-Chul;Lee, Doo Seok;Park, Ji Won;Oh, Jae Hwan;Chang, Hee Jin;Yoon, Mee Sun;Jeong, Jae-Uk;Jang, Hong Seok

    To perform a prospective phase II study to investigate the efficacy and safety of preoperative pelvic radiation therapy and concomitant small-field boost irradiation with 5-fluorouracil and leucovorin for 5 weeks in locally advanced rectal cancer patients. Sixty-nine patients with locally advanced, nonmetastatic, mid-to-lower rectal cancer were prospectively enrolled. They had received preoperative chemoradiation therapy and total mesorectal excision. Pelvic radiation therapy of 43.2 Gy in 24 fractions plus concomitant boost radiation therapy of 7.2 Gy in 12 fractions was delivered to the pelvis and tumor bed for 5 weeks. Two cycles of 5-fluorouracil and leucovorin were administered for 3 days in the first and fifth week of radiation therapy. The pathologic response, survival outcome, and treatment toxicity were evaluated for the study endpoints. Of 69 patients, 8 (11.6%) had a pathologically complete response. Downstaging rates were 40.5% for T classification and 68.1% for N ...


Mots clés : Colon-rectum; Traitements (Combinaison de traitements localisés et systémiques)

Menée in vitro et à l'aide de xénogreffes, cette étude évalue les effets cytotoxiques et radiosensibilisants de la darinaparsine, une cytotoxine dérivée de l'arsenic, sur les tumeurs solides

  • Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer
    Clinical Cancer Research, sous presse, 2012 (résumé)
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    Menée in vitro et à l'aide de xénogreffes, cette étude évalue les effets cytotoxiques et radiosensibilisants de la darinaparsine, une cytotoxine dérivée de l'arsenic, sur les tumeurs solides

    “Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer”

    • Tian, Junqiang;Zhao, Hongjuan;Nolley, Rosie;Reese, Stephen W.;Young, Sarah R.;Li, Xuejun;Peehl, Donna M.;Knox, Susan J.

    Purpose: Hypoxia is an important characteristic of the solid tumor microenvironment, and constitutes a barrier for effective radiotherapy. Here we studied the effects of Darinaparsin (DPS, an arsenic cytotoxin) on survival and radiosensitivity of tumor cells in vitro under normoxia and hypoxia and in vivo using xenograft models, compared to effects on normal tissues. Experimental Design: The cytotoxicity and radiosensitization of DPS were first tested in vitro in a variety of solid tumor cell lines under both normoxia and hypoxia, and compared with arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested in mouse models of xenograft tumors derived from tumor cell lines and clinical tumor specimens. The potential mechanisms of DPS effects, including ROS generation, cellular damage, and changes in global gene expression, were also investigated. Results : In comparison to ATO, DPS had significantly higher in ...


Mots clés : Cancer (général); Traitements (Combinaison de traitements localisés et systémiques)

Ressources et infrastructures (Traitements)

Cet article passe en revue différents concepts d'essais cliniques de phase II pour l'évaluation de traitements des tumeurs cérébrales

  • Phase 2 trial design in neuro-oncology revisited: a report from the RANO group
    The Lancet Oncology, Vol. 13 (5), pp. e196-e204, 2012 (résumé)
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    Cet article passe en revue différents concepts d'essais cliniques de phase II pour l'évaluation de traitements des tumeurs cérébrales

    “Phase 2 trial design in neuro-oncology revisited: a report from the RANO group”

    • Galanis, Evanthia;Wu, Wenting;Cloughesy, Timothy;Lamborn, Kathleen;Mann, Bhupinder;Wen, Patrick Y.;Reardon, David A.;Wick, Wolfgang;Macdonald, David;Armstrong, Terri S.;Weller, Michael;Vogelbaum, Michael;Colman, Howard;Sargent, Daniel J.;van den Bent, Martin J.;Gilbert, Mark;Chang, Susan

    Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents?which are competing for a small patient population, in view of the low incidence of primary brain tumours?draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further ...


Mots clés : Système nerveux central; Traitements (Ressources et infrastructures (Traitements))

Cet article analyse les raisons de la sous-représentation des patients âgés dans les essais cliniques de nouveaux traitements du cancer

Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

Cette étude analyse les principales caractéristiques de 96 346 essais cliniques enregistrés dans la base ClinicalTrials.gov jusqu'en septembre 2010

  • Characteristics of Clinical Trials Registered in ClinicalTrials.gov, 2007-2010
    JAMA: The Journal of the American Medical Association, Vol. 307 (17), pp. 1838-1847, 2012 (résumé)
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    Cette étude analyse les principales caractéristiques de 96 346 essais cliniques enregistrés dans la base ClinicalTrials.gov jusqu'en septembre 2010

    “Characteristics of Clinical Trials Registered in ClinicalTrials.gov, 2007-2010”

    • Califf, Robert M.;Zarin, Deborah A.;Kramer, Judith M.;Sherman, Rachel E.;Aberle, Laura H.;Tasneem, Asba

    Context Recent reports highlight gaps between guidelines-based treatment recommendations and evidence from clinical trials that supports those recommendations. Strengthened reporting requirements for studies registered with ClinicalTrials.gov enable a comprehensive evaluation of the national trials portfolio.Objective To examine fundamental characteristics of interventional clinical trials registered in the ClinicalTrials.gov database.Methods A data set comprising 96 346 clinical studies from ClinicalTrials.gov was downloaded on September 27, 2010, and entered into a relational database to analyze aggregate data. Interventional trials were identified and analyses were focused on 3 clinical specialties—cardiovascular, mental health, and oncology—that together encompass the largest number of disability-adjusted life-years lost in the United States.Main Outcome Measures Characteristics of registered clinical trials as reported data elements in the trial registry; how those ...


  • The Evolution of Trial Registries and Their Use to Assess the Clinical Trial Enterprise
    JAMA: The Journal of the American Medical Association, Vol. 307 (17), pp. 1861-1864, 2012 (éditorial)
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    Cette étude analyse les principales caractéristiques de 96 346 essais cliniques enregistrés dans la base ClinicalTrials.gov jusqu'en septembre 2010

    “The Evolution of Trial Registries and Their Use to Assess the Clinical Trial Enterprise”

    • Dickersin, Kay ; Rennie, Drummond


Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

Cet article passe en revue les travaux récents ayant évalué les effets des systèmes d'aide à la décision clinique sur la prise en charge des patients

  • Effect of Clinical Decision-Support Systems
    Annals of Internal Medicine, sous presse, 2012 (article en libre accès)
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    Cet article passe en revue les travaux récents ayant évalué les effets des systèmes d'aide à la décision clinique sur la prise en charge des patients

    “Effect of Clinical Decision-Support Systems”

    • Bright, Tiffani J.;Wong, Anthony;Dhurjati, Ravi;Bristow, Erin;Bastian, Lori;Coeytaux, Remy R.;Samsa, Gregory;Hasselblad, Vic;Williams, John W.;Musty, Michael D.;Wing, Liz;Kendrick, Amy S.;Sanders, Gillian D.;Lobach, David

    Background: Despite increasing emphasis on the role of clinical decision-support systems (CDSSs) for improving care and reducing costs, evidence to support widespread use is lacking.Purpose: To evaluate the effect of CDSSs on clinical outcomes, health care processes, workload and efficiency, patient satisfaction, cost, and provider use and implementation.Data Sources: MEDLINE, CINAHL, PsycINFO, Web of Science, and the Cochrane Database of Systematic Reviews through January 2011.Study Selection: Investigators independently screened reports to identify randomized trials published in English of electronic CDSSs that were implemented in clinical settings; used by providers to aid decision making at the point of care; and reported clinical, health care process, workload, relationship-centered, economic, or provider use outcomes.Data Extraction: Investigators extracted data about study design, participant characteristics, interventions, outcomes, and quality.Data Synthesis: 148 randomized, ...


Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

Cet article analyse les défis posés par le projet du gouvernement américain d'établir des bases de données cliniques électroniques à l'échelle nationale

  • Sharing Clinical Data Electronically
    JAMA: The Journal of the American Medical Association, Vol. 307 (16), pp. 1695-1696, 2012 (résumé)
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    Cet article analyse les défis posés par le projet du gouvernement américain d'établir des bases de données cliniques électroniques à l'échelle nationale

    “Sharing Clinical Data Electronically”

    • Adler-Milstein, Julia;Jha, Ashish K.

    The United States is undertaking an ambitious effort to wire the health care system. The goal is to build a nationwide information infrastructure to serve as the foundation for large and sustained improvements in performance. Widespread adoption of health information technology will support new care delivery models, such as patient-centered medical homes, alongside broader initiatives, such as performance reporting and public health surveillance. To enable the health information technology revolution, Congress allocated nearly $30 billion focused on 2 main goals: transitioning physicians and hospitals from paper-based to electronic systems and enabling these systems to interoperate, allowing clinical data to flow between health care organizations. The vision of complete patient information available across care delivery settings is compelling and central to a high-functioning health care system. However, the vision is deceptively simple: there are enormous challenges to enabling ...


Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

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