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Accueil Nota Bene Cancer V2 Numéro 129 du 27 Mars 2012 Traitements

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Nota Bene Cancer Numéro 129 du 27 Mars 2012 RSS

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Traitements localisés : découverte et développement

Menée sur 33 patients atteints d'un cancer du poumon non à petites cellules récidivant, cette étude évalue, du point de vue de la survie à long terme, la toxicité et l'efficacité d'une seconde radiothérapie combinée à une hyperthermie régionale et identifie les facteurs prédictifs associés à l'évolution de la maladie

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    Menée sur 33 patients atteints d'un cancer du poumon non à petites cellules récidivant, cette étude évalue, du point de vue de la survie à long terme, la toxicité et l'efficacité d'une seconde radiothérapie combinée à une hyperthermie régionale et identifie les facteurs prédictifs associés à l'évolution de la maladie

    “Re-irradiation plus regional hyperthermia for recurrent non-small cell lung cancer: A potential modality for inducing long-term survival in selected patients”

    • Ohguri, Takayuki;Imada, Hajime;Yahara, Katsuya;Moon, Seung Dae;Yamaguchi, Shinsaku;Yatera, Kazuhiro;Mukae, Hiroshi;Hanagiri, Takeshi;Tanaka, Fumihiro;Korogi, Yukunori

    Purpose : The purpose of this study was to assess the toxicity and efficacy of re-irradiation plus regional hyperthermia for recurrent NSCLC and to identify the predictors of long-term survival. Methods and materials : A total of 33 patients with recurrent NSCLC treated with re-irradiation plus regional hyperthermia were retrospectively analyzed. The median total dose of initial radiotherapy and re-irradiation were 70 Gy and 50 Gy, respectively. A median of 5 hyperthermia treatments using an 8-MHz radiofrequency-capacitive device were applied during re-irradiation in all patients. Results : Toxicity of Grade 3 was seen in 3 (9%) patients, and no Grade 4 or 5 toxicity was observed. The median overall survival, local control, and disease progression-free survival times after re-irradiation were 18.1, 12.1, and 6.7 months, respectively. Eight patients achieved a long-term survival (more than 3 years after re-irradiation), and 4 of them underwent a third round of irradiation for ...


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

Cet article fait le point sur les études récentes concernant le traitement des cancers par la photothérapie dynamique combinée à des inhibiteurs de l'angiogenèse

  • Angiogenesis inhibition for the improvement of photodynamic therapy: The revival of a promising idea
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, sous presse, 2012 (résumé)
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    Cet article fait le point sur les études récentes concernant le traitement des cancers par la photothérapie dynamique combinée à des inhibiteurs de l'angiogenèse

    “Angiogenesis inhibition for the improvement of photodynamic therapy: The revival of a promising idea”

    • Weiss, Andrea;den Bergh, Hubert van;Griffioen, Arjan W.;Nowak-Sliwinska, Patrycja

    Photodynamic therapy (PDT) is a minimally invasive form of treatment, which is clinically approved for the treatment of angiogenic disorders, including certain forms of cancer and neovascular eye diseases. Although the concept of PDT has existed for a long time now, it has never made a solid entrance into the clinical management of cancer. This is likely due to secondary tissue reactions, such as inflammation and neoangiogenesis. The recent development of clinically effective angiogenesis inhibitors has lead to the initiation of research on the combination of PDT with such angiostatic targeted therapies. Preclinical studies in this research field have shown promising results, causing a revival in the field of PDT. This review reports on the current research efforts on PDT and vascular targeted combination therapies. Different combination strategies with angiogenesis inhibition and vascular targeting approaches are discussed. In addition, the concept of increasing PDT selectivity by ...


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

Traitements localisés : applications cliniques

Mené sur 35 patients atteints d'un glioblastome et ayant subi une résection chirurgicale ou une biopsie, cet essai prospectif de phase II évalue l'efficacité et la toxicité d'une radiochirurgie stéréotaxique en combinaison avec une radiothérapie standard pour traiter des tumeurs cérébrales à haut risque identifiées au moyen d'une spectroscopie par résonance magnétique

  • Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy–Defined High-Risk Tumor Volumes in Patients with Glioblastoma Multiforme
    International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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    Mené sur 35 patients atteints d'un glioblastome et ayant subi une résection chirurgicale ou une biopsie, cet essai prospectif de phase II évalue l'efficacité et la toxicité d'une radiochirurgie stéréotaxique en combinaison avec une radiothérapie standard pour traiter des tumeurs cérébrales à haut risque identifiées au moyen d'une spectroscopie par résonance magnétique

    “Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy–Defined High-Risk Tumor Volumes in Patients with Glioblastoma Multiforme”

    • Einstein, Douglas B.;Wessels, Barry;Bangert, Barbara;Fu, Pingfu;Nelson, A. Dennis;Cohen, Mark;Sagar, Stephen;Lewin, Jonathan;Sloan, Andrew;Zheng, Yiran;Williams, Jordonna;Colussi, Valdir;Vinkler, Robert;Maciunas, Robert

    To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The ...


Mots clés : Système nerveux central; Traitements (Traitements localisés : applications cliniques)

Menée entre 2002 et 2011 sur 73 patients atteints d'un cancer de la prostate unilatéral à risque faible ou intermédiaire (durée médiane de suivi : 3,7 ans), cette étude évalue les résultats oncologiques et fonctionnels d'une cryothérapie focale

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    Menée entre 2002 et 2011 sur 73 patients atteints d'un cancer de la prostate unilatéral à risque faible ou intermédiaire (durée médiane de suivi : 3,7 ans), cette étude évalue les résultats oncologiques et fonctionnels d'une cryothérapie focale

    “Focal Cryotherapy for Clinically Unilateral, Low-Intermediate Risk Prostate Cancer in 73 Men with a Median Follow-Up of 3.7 Years”

    • Duke, Bahn;Andre Luis de Castro, Abreu;Inderbir, S. Gill;Andrew, J. Hung;Paul, Silverman;Mitchell, E. Gross;Gary, Lieskovsky;Osamu, Ukimura

    Background : Evolution of cryotherapy for prostate cancer is likely to result in parenchyma-sparing modifications adjacent to the urethra and neurovascular bundle. Results of initial series of focal therapy to minimize cryosurgery-related morbidity without compromising oncologic control have been encouraging, but limited in short-term outcomes. Objective : To retrospectively report (1) median 3.7-yr follow-up experience of primary focal cryotherapy for clinically unilateral prostate cancer with oncologic and functional outcomes, and (2) matched-pair analysis with contemporaneous patients undergoing radical prostatectomy (RP). Design, setting, and participants : Over 8.5 yr (September 2002 to March 2011), focal cryoablation (defined as ablation of one lobe) was performed in 73 carefully selected patients with biopsy-proven, clinically unilateral, low-intermediate risk prostate cancer. All patients underwent transrectal ultrasound (TRUS) and Doppler-guided sextant and targeted biopsies ...


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

A partir de données cliniques portant sur 192 patients atteints d'un cancer localisé du pancréas et traités entre 1980 et 2009, cette étude monocentrique japonaise évalue, du point de vue de la survie globale et du contrôle local de la maladie, l'efficacité et la toxicité d'une radiothérapie intra-opératoire combinée ou non à une radiothérapie externe et analyse les facteurs pronostiques associés

  • Intraoperative Radiotherapy for Pancreatic Cancer: 30-Year Experience in a Single Institution in Japan
    International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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    A partir de données cliniques portant sur 192 patients atteints d'un cancer localisé du pancréas et traités entre 1980 et 2009, cette étude monocentrique japonaise évalue, du point de vue de la survie globale et du contrôle local de la maladie, l'efficacité et la toxicité d'une radiothérapie intra-opératoire combinée ou non à une radiothérapie externe et analyse les facteurs pronostiques associés

    “Intraoperative Radiotherapy for Pancreatic Cancer: 30-Year Experience in a Single Institution in Japan”

    • Jingu, Keiichi;Tanabe, Takaya;Nemoto, Kenji;Ariga, Hisanori;Umezawa, Rei;Ogawa, Yoshihiro;Takeda, Ken;Koto, Masashi;Sugawara, Toshiyuki;Kubozono, Masaki;Shimizu, Eiji;Abe, Keiko;Yamada, Shogo

    To analyze retrospectively the results of intraoperative radiotherapy (IORT) with or without external beam radiotherapy (± EBRT) for localized pancreatic cancer in the past three decades and to analyze prognostic factors by multivariate analysis. Records for 322 patients with pancreatic cancer treated by IORT ± EBRT in Tohoku University Hospital between 1980 and 2009 were reviewed. One hundred ninety-two patients who had no distant organ metastases or dissemination at the time of laparotomy were enrolled in the present study. Eighty-three patients underwent gross total resection (R0: 48 patients, R1: 35 patients), and 109 patients underwent only biopsy or palliative resection. Fifty-five patients underwent adjuvant EBRT, and 124 underwent adjuvant chemotherapy. The median doses of IORT and EBRT were 25 and 40 Gy, respectively. The median follow-up period was 37.5 months. At the time of the analysis, 166 patients had disease recurrence, and 35 patients had local failure. The 2-year ...


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

Traitements systémiques : découverte et développement

Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'intérêt de la liquiritigénine, un agoniste du récepteur β des estrogènes, pour le traitement de patients atteints d'un gliome

  • Therapeutic significance of estrogen receptor β agonists in gliomas
    Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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    Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'intérêt de la liquiritigénine, un agoniste du récepteur β des estrogènes, pour le traitement de patients atteints d'un gliome

    “Therapeutic significance of estrogen receptor β agonists in gliomas”

    • Sareddy, Gangadhara Reddy;Nair, Binoj C;Gonugunta, Vijaya K;Zhang, Quan-guang;Brenner, Andrew J;Brann, Darrell W;Tekmal, Rajeshwar Rao;Vadlamudi, Ratna K.

    Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two ER subtypes: ERβ, that functions as tumor promoter and ERβ that function as tumor suppressor. We examined the potential use of ERβ agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERβ with little or no ERβ. Treatment of glioma cells with ERβ agonists resulted in significant decrease in proliferation. IHC analysis of tumor tissues revealed that ERβ expression is down regulated in high-grade gliomas. We found that ERβ agonists promote both expression and tumor suppressive functions of ERβ in glioma cells. Liquiritigenin, a plant-derived ERβ agonist significantly reduced in vivo tumor growth in a xenograft model. Compared to control mice, animals ...


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

Menée sur 129 patientes atteintes d'un cancer métastatique du sein, cette étude évalue, du point de vue du taux de réponse objective, l'ajout de doxorubicine liposomale pégylée au carboplatine, avec ou sans trastuzumab

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    Menée sur 129 patientes atteintes d'un cancer métastatique du sein, cette étude évalue, du point de vue du taux de réponse objective, l'ajout de doxorubicine liposomale pégylée au carboplatine, avec ou sans trastuzumab

    “Pegylated liposomal doxorubicin plus carboplatin in patients with metastatic breast cancer: a phase II study”

    • Collea, R. P.;Kruter, F. W.;Cantrell, J. E.;George, T. K.;Kruger, S.;Favret, A. M.;Lindquist, D. L.;Melnyk, A. M.;Pluenneke, R. E.;Shao, S. H.;Crockett, M. W.;Asmar, L.;O’Shaughnessy, J.

    Background: We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin).Patients and methods: Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor-2 status. Treatment: PLD 30 mg/m2 followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab.Results: Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3–4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; ...


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

Mené sur 17 patients atteints d'un sarcome de Kaposi lié à une infection par le VIH, cet essai de phase II évalue la toxicité et l'activité antitumorale du bevacizumab

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    Mené sur 17 patients atteints d'un sarcome de Kaposi lié à une infection par le VIH, cet essai de phase II évalue la toxicité et l'activité antitumorale du bevacizumab

    “Phase II Study of Bevacizumab in Patients With HIV-Associated Kaposi's Sarcoma Receiving Antiretroviral Therapy”

    • Uldrick, Thomas S.;Wyvill, Kathleen M.;Kumar, Pallavi;O'Mahony, Deirdre;Bernstein, Wendy;Aleman, Karen;Polizzotto, Mark N.;Steinberg, Seth M.;Pittaluga, Stefania;Marshall, Vickie;Whitby, Denise;Little, Richard F.;Yarchoan, Robert

    Purpose Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti–VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS.Patients and Methods Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately.Results Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T1), 13 patients ...


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

Mené sur 192 patients atteints d'un carcinome à cellules claires du rein, cet essai de phase II évalue, du point de vue de la durée avant progression tumorale, deux modes d'administration du sunitinib

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    Mené sur 192 patients atteints d'un carcinome à cellules claires du rein, cet essai de phase II évalue, du point de vue de la durée avant progression tumorale, deux modes d'administration du sunitinib

    “Randomized Phase II Trial of Sunitinib on an Intermittent Versus Continuous Dosing Schedule As First-Line Therapy for Advanced Renal Cell Carcinoma”

    • Motzer, Robert J.;Hutson, Thomas E.;Olsen, Mark R.;Hudes, Gary R.;Burke, John M.;Edenfield, William J.;Wilding, George;Agarwal, Neeraj;Thompson, John A.;Cella, David;Bello, Akintunde;Korytowsky, Beata;Yuan, Jinyu;Valota, Olga;Martell, Bridget;Hariharan, Subramanian;Figlin, Robert A.

    Purpose Sunitinib has shown antitumor activity with a manageable safety profile as metastatic renal cell carcinoma (RCC) treatment, when given by the standard intermittent schedule as well as a continuous daily dosing (CDD) schedule. A trial was conducted to compare the schedules.Patients and Methods Patients with treatment-naive, clear cell advanced RCC were randomly assigned 1:1 to receive sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2; n = 146) or 37.5 mg/d on the CDD schedule (n = 146) for up to 2 years. The primary end point was time to tumor progression.Results Median time to tumor progression was 9.9 months for schedule 4/2 and 7.1 months for the CDD schedule (hazard ratio, 0.77; 95% CI, 0.57 to 1.04; P = .090). No significant difference was observed in overall survival (23.1 v 23.5 months; P = .615), commonly reported adverse events, or patient-reported kidney cancer symptoms. Schedule 4/2 was statistically superior to CDD in time to ...


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

Cet article passe en revue les défis posés par le ciblage des cellules souches cancéreuses pour le traitement des cancers du poumon

  • Can lung cancer stem cells be targeted for therapies?
    Cancer treatment reviews, sous presse, 2012 (résumé)
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    Cet article passe en revue les défis posés par le ciblage des cellules souches cancéreuses pour le traitement des cancers du poumon

    “Can lung cancer stem cells be targeted for therapies?”

    • Wu, Xiaodan;Chen, Hong;Wang, Xiangdong

    Lung cancer is the leading cause of cancer death, with a poor prognosis. Lung cancer stem cells (CSCs) are proposed as one of therapeutic targets for lung cancer. It is important to understand the exact role of lung CSC subpopulations in tumor initiation, recurrence, drug resistance and metastasis and explore biomarkers, signaling pathways and differentiation regulation specific to lung CSCs. Numerous measures targeting lung CSCs, e.g. genomics, proteomics and bioinformatics, have been used to investigate molecular mechanisms, eradicate cancer cells, and improve patient outcome. The present review overviewed the biological functions, biomarkers, signal pathways, differentiation regulation, genomics and proteomics, targeting roles of lung CSCs and related information on other CSCs as references. There are still a number of challenges to translate the research and understanding of lung CSCs to clinical applications and therapies, identify lung CSCs-specific and dynamic network ...


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

Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, cette étude évalue l'efficacité d'une stratégie thérapeutique combinant un petit ARN interférent spécifique du récepteur EGFR et un inhibiteur de tyrosine kinase, tel que l'afatinib, ou le cetuximab

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    Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, cette étude évalue l'efficacité d'une stratégie thérapeutique combinant un petit ARN interférent spécifique du récepteur EGFR et un inhibiteur de tyrosine kinase, tel que l'afatinib, ou le cetuximab

    “Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab”

    • Chen, Gang;Kronenberger, Peter;Teugels, Erik;Adaku Umelo, Ijeoma;De Greve, Jacques

    BACKGROUND:The epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations are resistant to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs) or a monoclonal antibody cetuximab.METHODS:NSCLC cells (cell lines HCC827, H292, H358, H1650 and H1975) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity and apoptotic ...


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

Menée sur des modèles murins d'adénocarcinome canalaire du pancréas, cette étude identifie un constituant du stroma qui bloque l'accès des molécules cytotoxiques à la tumeur, puis montre qu'un traitement enzymatique ciblé sur ce constituant permet d'augmenter la durée de survie associée à une chimiothérapie à la gemcitabine

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    Menée sur des modèles murins d'adénocarcinome canalaire du pancréas, cette étude identifie un constituant du stroma qui bloque l'accès des molécules cytotoxiques à la tumeur, puis montre qu'un traitement enzymatique ciblé sur ce constituant permet d'augmenter la durée de survie associée à une chimiothérapie à la gemcitabine

    “Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma”

    • Provenzano, Paolo P;Cuevas, Carlos;Chang, Amy E;Goel, Vikas K;Von Hoff, Daniel D;Hingorani, Sunil R

    Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival. º Extremely high interstitial fluid pressures (IFPs) induce vascular collapse in PDA º ...


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    Menée sur des modèles murins d'adénocarcinome canalaire du pancréas, cette étude identifie un constituant du stroma qui bloque l'accès des molécules cytotoxiques à la tumeur, puis montre qu'un traitement enzymatique ciblé sur ce constituant permet d'augmenter la durée de survie associée à une chimiothérapie à la gemcitabine

    “Targeting Tumor Architecture to Favor Drug Penetration: A New Weapon to Combat Chemoresistance in Pancreatic Cancer?”

    • Yu, Man ; Tannock, Ian F

    Pancreatic ductal adenocarcinoma (PDA) responds poorly to chemotherapy. In this issue of Cancer Cell, Provenzano et al. identify hyaluronan as a pivotal determinant of elevated interstitial fluid pressures (IFP) and vascular collapse in PDA. PEGPH20 treatment ablates stromal hyaluronan, normalizes IFP, and increases accessibility of tumor cells to anticancer drugs.


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

Cette étude met en évidence un mécanisme permettant de rendre compte du faible intérêt d'un traitement à l'interleukine 12 chez les patients atteints d'un lymphome folliculaire

  • IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Cette étude met en évidence un mécanisme permettant de rendre compte du faible intérêt d'un traitement à l'interleukine 12 chez les patients atteints d'un lymphome folliculaire

    “IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma”

    • Yang, Zhi-Zhang;Grote, Deanna M.;Ziesmer, Steven C.;Niki, Toshiro;Hirashima, Mitsuomi;Novak, Anne J.;Witzig, Thomas E.;Ansell, Stephen M.

    The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell ...


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

Cet article passe en revue les perspectives offertes par la combinaison de thérapies ciblées et d'immunothérapies pour le traitement des cancers

  • Combining immunotherapy and targeted therapies in cancer treatment
    Nature Reviews Cancer, Vol. 12 (4), pp. 237-251, 2012 (article en libre accès)
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    Cet article passe en revue les perspectives offertes par la combinaison de thérapies ciblées et d'immunothérapies pour le traitement des cancers

    “Combining immunotherapy and targeted therapies in cancer treatment”

    • Vanneman, Matthew;Dranoff, Glenn

    During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with ...


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

Menée sur des cellules de tumeurs épithéliales et de leucémie, cette étude montre qu'une exposition transitoire à des inihibiteurs de méthylation de l'ADN, la décitabine et l'azacitidine, induit une réponse antitumorale, notamment l'inhibition de sous-populations de cellules souches cancéreuses

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    Menée sur des cellules de tumeurs épithéliales et de leucémie, cette étude montre qu'une exposition transitoire à des inihibiteurs de méthylation de l'ADN, la décitabine et l'azacitidine, induit une réponse antitumorale, notamment l'inhibition de sous-populations de cellules souches cancéreuses

    “Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells”

    • Tsai, Hsing-Chen;Li, Huili;Van Neste, Leander;Cai, Yi;Robert, Carine;Rassool, Feyruz V;Shin, James J;Harbom, Kirsten M;Beaty, Robert;Pappou, Emmanouil;Harris, James;Yen, Ray-Whay Chiu;Ahuja, Nita;Brock, Malcolm V;Stearns, Vered;Feller-Kopman, David;Yarmus, Lonny B;Lin, Yi-Chun;Welm, Alana L;Issa, Jean-Pierre;Minn, Il;Matsui, William;Jang, Yoon-Young;Sharkis, Saul J;Baylin, Stephen B;Zahnow, Cynthia A

    Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor memory response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management. º Transient DAC or AZA sustains antitumor responses and reduces ...


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

Cet article passe en revue le rôle des polymérases PARP dans les mécanismes de réponse aux atteintes à l'ADN et analyse les développements actuels d'inhibiteurs de PARP pour le traitement des cancers

  • PARPs and the DNA damage response
    Carcinogenesis, sous presse, 2012 (résumé)
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    Cet article passe en revue le rôle des polymérases PARP dans les mécanismes de réponse aux atteintes à l'ADN et analyse les développements actuels d'inhibiteurs de PARP pour le traitement des cancers

    “PARPs and the DNA damage response”

    • Sousa, Fabricio G.;Matuo, Renata;Soares, Daniele Grazziotin;Escargueil, Alexandre E.;Henriques, João A.P.;Larsen, Annette K.;Saffi, Jenifer

    ADP-ribosylation is an important posttranslational modification catalyzed by a variety of enzymes, including poly(ADP-ribose) polymerases (PARPs), which use NAD+ as a substrate to synthesize and transfer ADP-ribose units to acceptor proteins. The PARP family members possess a variety of structural domains, span a wide range of functions and localize to various cellular compartments. Among the molecular actions attributed to PARPs, their role in the DNA damage response (DDR) has been widely documented. In particular, PARPs 1-3 are involved in several cellular processes that respond to DNA lesions, which include DNA damage recognition, signaling and repair as well as local transcriptional blockage, chromatin remodeling and cell death induction. However, how these enzymes are able to participate in such numerous and diverse mechanisms in response to DNA damage is not fully understood. Herein, the DDR functions of PARPs 1-3 and the emerging roles of poly(ADP-ribose) polymers (PAR) in DNA ...


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

Mené sur 22 patients atteints d'un lymphome non hodgkinien CD20+ récidivant ou d'une leucémie lymphocytaire chronique, cet essai de phase I évalue la toxicité et l'activité antitumorale de l'obinutuzumab, un anticorps anti-CD20

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    Mené sur 22 patients atteints d'un lymphome non hodgkinien CD20+ récidivant ou d'une leucémie lymphocytaire chronique, cet essai de phase I évalue la toxicité et l'activité antitumorale de l'obinutuzumab, un anticorps anti-CD20

    “A phase I study of obinutuzumab induction followed by two years of maintenance in patients with relapsed CD20-positive B-cell malignancies”

    • Sehn, Laurie H.;Assouline, Sarit E.;Stewart, Douglas A.;Mangel, Joy;Gascoyne, Randy D.;Fine, Gregg;Frances-Lasserre, Susan;Carlile, David J.;Crump, Michael

    This phase I study evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of obinutuzumab (GA101), a glycoengineered type II anti-CD20 monoclonal antibody administered as induction followed by two years of maintenance. Cohorts of 3-6 patients received obinutuzumab (200-2000 mg) intravenously weekly for 4 weeks. Patients with a complete or partial response (or stable disease and clinical benefit) continued to receive obinutuzumab every 3 months for a maximum of 8 doses. Twenty-two patients with relapsed CD20-positive non-Hodgkin lymphoma or chronic lymphocytic leukemia with an indication for treatment and no therapy of higher priority were enrolled. Patients received a median of 4 prior regimens; 86% had received at least one rituximab-containing regimen. No dose limiting or unexpected adverse events were observed. Infusion-related reactions were most common (all grades 73%, grade 3/4 18%), followed by infection (32%), pyrexia (23%), neutropenia (23%), headache ...


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

Cet article passe en revue les stratégies mises en œuvre, depuis les études précliniques jusqu'aux essais chez l'humain, pour développer des traitements du cancer à base d'anticorps monoclonaux

  • Antibody therapy of cancer
    Nature Reviews Cancer, Vol. 12 (4), pp. 278-287, 2012 (article en libre accès)
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    Cet article passe en revue les stratégies mises en œuvre, depuis les études précliniques jusqu'aux essais chez l'humain, pour développer des traitements du cancer à base d'anticorps monoclonaux

    “Antibody therapy of cancer”

    • Scott, Andrew M.;Wolchok, Jedd D.;Old, Lloyd J.

    The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody–drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.


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

Cet article passe en revue les perpectives offertes par les connaissances relatives aux cellules dendritiques pour le développement d'immunothérapies du cancer

  • Cancer immunotherapy via dendritic cells
    Nature Reviews Cancer, Vol. 12 (4), pp. 265-277, 2012 (article en libre accès)
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    Cet article passe en revue les perpectives offertes par les connaissances relatives aux cellules dendritiques pour le développement d'immunothérapies du cancer

    “Cancer immunotherapy via dendritic cells”

    • Palucka, Karolina;Banchereau, Jacques

    Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.


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

Menée in vitro et à l'aide de xénogreffes, cette étude identifie un mécanisme de résistance à un nouveau composé appelé MLN4924, une petite molécule inhibant l'enzyme NAE

  • Treatment-Emergent Mutations in NAE
    Cancer cell, Vol. 21 (3), pp. 388-401, 2012 (article en libre accès)
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    Menée in vitro et à l'aide de xénogreffes, cette étude identifie un mécanisme de résistance à un nouveau composé appelé MLN4924, une petite molécule inhibant l'enzyme NAE

    “Treatment-Emergent Mutations in NAE”

    • Milhollen, Michael A;Thomas, Michael P;Narayanan, Usha;Traore, Tary;Riceberg, Jessica;Amidon, Benjamin S;Bence, Neil F;Bolen, Joseph B;Brownell, James;Dick, Lawrence R;Loke, Huay-Keng;McDonald, Alice A;Ma, Jingya;Manfredi, Mark G;Sells, Todd B;Sintchak, Mike D;Yang, Xiaofeng;Xu, Qing;Koenig, Erik M;Gavin, James M;Smith, Peter G

    MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAE β as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAE β mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAE β mutations. º Treatment-emergent mutations in NAE β confer resistance to MLN4924 º Amino acid substitution A171T ...


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

Menée in vitro et à l'aide de xénogreffes, cette étude suggère qu'un anticorps monoclonal ciblé sur l'éphrine B2 pourrait, seul ou en combinaison, être efficace contre l'angiogenèse

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    Menée in vitro et à l'aide de xénogreffes, cette étude suggère qu'un anticorps monoclonal ciblé sur l'éphrine B2 pourrait, seul ou en combinaison, être efficace contre l'angiogenèse

    “Blocking ephrin-B2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth”

    • Abéngozar, María Angeles;de Frutos, Sergio;Ferreiro, Sergio;Soriano, Joaquím;Perez-Martinez, Manuel;Olmeda, David;Marenchino, Marco;Cañamero, Marta;Ortega, Sagrario;Megias, Diego;Rodriguez, Antonio;Martínez-Torrecuadrada, Jorge L.

    Membrane-anchored ephrinB2 and its receptor EphB4 are involved in the formation of blood and lymphatic vessels in normal and pathological conditions. Eph/ephrin activation requires cell-cell interactions and leads to bidirectional signaling pathways in both ligand- and receptor-expressing cells. To investigate the functional consequences of blocking ephrinB2 activity, two highly specific human single-chain Fv (scFv) antibody fragments against ephrinB2 were generated and characterized. Both antibody fragments suppressed endothelial cell migration and tube formation in vitro in response to VEGF and provoked abnormal cell motility and actin cytoskeleton alterations in isolated endothelial cells. As only one of them (B11) competed for binding of ephrinB2 to EphB4, these data suggest an EphB-receptor-independent blocking mechanism. Anti-ephrinB2 therapy reduced VEGF-induced neovascularization in a mouse Matrigel plug assay. Moreover, systemic administration of ephrinB2-blocking antibodies ...


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

Traitements systémiques : applications cliniques

Cet article passe en revue les travaux récents sur le traitement des tumeurs germinales du testicule

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    Cet article passe en revue les travaux récents sur le traitement des tumeurs germinales du testicule

    “The Contemporary Role of Chemotherapy for Advanced Testis Cancer: A Systematic Review of the Literature”

    • Fabio, Calabrò;Peter, Albers;Carsten, Bokemeyer;Chris, Martin;Lawrence, H. Einhorn;Alan, Horwich;Susanne, Krege;Hans Joachim, Schmoll;Cora, N. Sternberg;Gedske, Daugaard

    Context: Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basis of randomised trials and prognostic factors. Objective: This review summarises the evolving role of chemotherapy in the treatment of previously treated and untreated patients with metastatic GCTs and outlines the current standard treatment. Evidence acquisition: Randomised and nonrandomised trials of first-line, salvage, and palliative therapy were reviewed. Evidence synthesis: Three cycles of standard bleomycin, etoposide, and platinum (BEP) can be considered the gold-standard treatment in good-risk patients, and four cycles of the same combination can result in cure in approximately 80% of intermediate-risk and 50% of poor-risk patients. The routine use of high-dose chemotherapy in patients with intermediate- or poor-prognosis GCT has not improved treatment outcome, but the role of ...


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

Cet article passe en revue les travaux récents sur le traitement et la prise en charge des cancers métastatiques du sein

  • Current approaches to the management of Her2-negative metastatic breast cancer
    Breast Cancer Research, Vol. 14 (2), pp. 205, 2012 (article en libre accès)
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    Cet article passe en revue les travaux récents sur le traitement et la prise en charge des cancers métastatiques du sein

    “Current approaches to the management of Her2-negative metastatic breast cancer”

    • Gogineni, Keerthi;DeMichele, Angela

    While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while maintaining quality of life and physical function. Optimal management of MBC balances a multitude of factors, including a woman's performance status, social support, symptoms, disease burden, prior therapies, and surrogates for tumor biology. Choosing the most appropriate initial therapy and subsequent sequence of treatments demands flexibility as goals and patient preferences may change. Knowledge of the estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor status of the metastatic tumor has become critical to determining the optimal treatment strategy in the metastatic setting as targeted therapeutic approaches are developed. Patients with ER+ or PR+ breast cancer or both have a wide array of hormonal therapy options that can forestall the use of cytotoxic therapies, although rapidly progressive phenotypes ...


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

A partir de données portant sur des patients atteints d'un carcinome métastatique à cellules rénales et inclus dans l'essai de phase III RECORD-1, cette étude analyse de façon rétrospective la toxicité et l'efficacité de l'évérolimus chez les patients qui avaient préalablement interrompu un traitement par inhibiteurs de tyrosine kinase de VEGFR pour cause de toxicité

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    A partir de données portant sur des patients atteints d'un carcinome métastatique à cellules rénales et inclus dans l'essai de phase III RECORD-1, cette étude analyse de façon rétrospective la toxicité et l'efficacité de l'évérolimus chez les patients qui avaient préalablement interrompu un traitement par inhibiteurs de tyrosine kinase de VEGFR pour cause de toxicité

    “Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis”

    • Bracarda, S.;Hutson, T. E.;Porta, C.;Figlin, R. A.;Calvo, E.;Grunwald, V.;Ravaud, A.;Motzer, R.;Kim, D.;Anak, O.;Panneerselvam, A.;Escudier, B.

    Background: A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity. Methods: Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan–Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model. Results: In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS ...


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

Mené sur 875 patients atteints d'un cancer de la prostate à haut risque, cet essai international (STAMPEDE) évalue, du point de vue de la survie globale, l'ajout de célécoxib à une hormonothérapie

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    Mené sur 875 patients atteints d'un cancer de la prostate à haut risque, cet essai international (STAMPEDE) évalue, du point de vue de la survie globale, l'ajout de célécoxib à une hormonothérapie

    “Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial”

    • James, Nicholas D.;Sydes, Matthew R.;Mason, Malcolm D.;Clarke, Noel W.;Anderson, John;Dearnaley, David P.;Dwyer, John;Jovic, Gordana;Ritchie, Alastair W. S.;Russell, J. Martin;Sanders, Karen;Thalmann, George N.;Bertelli, Gianfilippo;Birtle, Alison J.;O'Sullivan, Joe M.;Protheroe, Andrew;Sheehan, Denise;Srihari, Narayanan;Parmar, Mahesh K. B.

    Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE?an international, open-label, randomised controlled trial?uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven ...


  • The STAMPEDE trial and celecoxib: how to adapt?
    The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
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    Mené sur 875 patients atteints d'un cancer de la prostate à haut risque, cet essai international (STAMPEDE) évalue, du point de vue de la survie globale, l'ajout de célécoxib à une hormonothérapie

    “The STAMPEDE trial and celecoxib: how to adapt?”

    • Armstrong, Andrew J.


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

Menés sur 697 et 129 patients atteints d'un adénocarcinome pulmonaire de stade avancé, ces deux essais évaluent l'efficacité de l'afatinib, une molécule se liant de façon irréversible aux récepteurs EGFR et HER2

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    Menés sur 697 et 129 patients atteints d'un adénocarcinome pulmonaire de stade avancé, ces deux essais évaluent l'efficacité de l'afatinib, une molécule se liant de façon irréversible aux récepteurs EGFR et HER2

    “Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial”

    • Yang, James Chih-Hsin;Shih, Jin-Yuan;Su, Wu-Chou;Hsia, Te-Chun;Tsai, Chun-Ming;Ou, Sai-Hong Ignatius;Yu, Chung-Jen;Chang, Gee-Chen;Ho, Ching-Liang;Sequist, Lecia V.;Dudek, Arkadiusz Z.;Shahidi, Mehdi;Cong, Xiuyu Julie;Lorence, Robert M.;Yang, Pan-Chyr;Miller, Vincent A.

    Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0?2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 ...


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    Menés sur 697 et 129 patients atteints d'un adénocarcinome pulmonaire de stade avancé, ces deux essais évaluent l'efficacité de l'afatinib, une molécule se liant de façon irréversible aux récepteurs EGFR et HER2

    “Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial”

    • Miller, Vincent A. ; Hirsh, Vera ; Cadranel, Jacques ; Chen, Yuh-Min ; Park, Keunchil ; Kim, Sang-We ; Zhou, Caicun ; Su, Wu-Chou ; Wang, Mengzhao ; Sun, Yan ; Heo, Dae Seog ; Crino, Lucio ; Tan, Eng-Huat ; Chao, Tsu-Yi ; Shahidi, Mehdi ; Cong, Xiuyu Julie ; Lorence, Robert M. ; Yang, James Chih-Hsin

    Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0?2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0?1vs2). Investigators, patients, and the trial sponsor were masked to ...


  • A new generation of EGFR tyrosine-kinase inhibitors in NSCLC
    The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
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    Menés sur 697 et 129 patients atteints d'un adénocarcinome pulmonaire de stade avancé, ces deux essais évaluent l'efficacité de l'afatinib, une molécule se liant de façon irréversible aux récepteurs EGFR et HER2

    “A new generation of EGFR tyrosine-kinase inhibitors in NSCLC”

    • Hirsch, Fred R. ; Bunn, Paul A.


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

Mené sur 72 patients atteints d'un mélanome avancé avec métastases cérébrales, cet essai de phase II évalue l'efficacité de l'ipilimumab pour contrôler la maladie après 12 semaines de traitement

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    Mené sur 72 patients atteints d'un mélanome avancé avec métastases cérébrales, cet essai de phase II évalue l'efficacité de l'ipilimumab pour contrôler la maladie après 12 semaines de traitement

    “Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial”

    • Margolin, Kim;Ernstoff, Marc S.;Hamid, Omid;Lawrence, Donald;McDermott, David;Puzanov, Igor;Wolchok, Jedd D.;Clark, Joseph I.;Sznol, Mario;Logan, Theodore F.;Richards, Jon;Michener, Tracy;Balogh, Agnes;Heller, Kevin N.;Hodi, F. Stephen

    Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial ...


  • Treatment of brain metastases in patients with melanoma
    The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
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    Mené sur 72 patients atteints d'un mélanome avancé avec métastases cérébrales, cet essai de phase II évalue l'efficacité de l'ipilimumab pour contrôler la maladie après 12 semaines de traitement

    “Treatment of brain metastases in patients with melanoma”

    • Fisher, Rosalie ; Larkin, James


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

Combinaison de traitements localisés et systémiques

Cet article fait le point sur les études récentes concernant les différentes stratégies de préservation du larynx dans le traitement d'un cancer de cet organe

  • Larynx preservation
    Current Opinion in Oncology, sous presse, 2012 (résumé)
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    Cet article fait le point sur les études récentes concernant les différentes stratégies de préservation du larynx dans le traitement d'un cancer de cet organe

    “Larynx preservation”

    • Lefebvre, Jean-Louis

    Purpose of review: Organ preservation, in particular larynx preservation, is a major challenge that has been evaluated during the past 3 decades. This review took in consideration the most recently published articles on this topic. Recent findings: There are no new data on this topic but mainly confirming data. Most of the reports underscored that there was still a place for upfront surgery (either partial or total laryngectomy). Nonsurgical approaches are radiotherapy alone or chemotherapy-based protocols with either induction or concomitant chemotherapy added to radiotherapy (with conventional or accelerated fractionation). Different authors underscored that daily practice must follow carefully the selection of patients and monitoring of treatment when applying protocols evaluated in randomized clinical trials. Summary: Larynx preservation is an undisputable advance in larynx cancer management. For early diseases, either surgery (open or endoscopic) or irradiation may control the ...


Mots clés : Voies aérodigestives supérieures; Traitements (Combinaison de traitements localisés et systémiques)

Mené sur 52 patients atteints d'un lymphome hodgkinien de stade précoce et présentant une atteinte médiastinale, cette étude évalue les résultats dosimétriques et cliniques d'une radiothérapie avec modulation d'intensité consécutive à une chimiothérapie

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    Mené sur 52 patients atteints d'un lymphome hodgkinien de stade précoce et présentant une atteinte médiastinale, cette étude évalue les résultats dosimétriques et cliniques d'une radiothérapie avec modulation d'intensité consécutive à une chimiothérapie

    “Dosimetric and Clinical Outcomes of Involved-Field Intensity-Modulated Radiotherapy After Chemotherapy for Early-Stage Hodgkin’s Lymphoma with Mediastinal Involvement”

    • Lu, Ning-Ning;Li, Ye-Xiong;Wu, Run-Ye;Zhang, Xi-Mei;Wang, Wei-Hu;Jin, Jing;Song, Yong-Wen;Fang, Hui;Ren, Hua;Wang, Shu-Lian;Liu, Yue-Ping;Liu, Xin-Fan;Chen, Bo;Dai, Jian-Rong;Yu, Zi-Hao

    To evaluate the dosimetric and clinical outcomes of involved-field intensity-modulated radiotherapy (IF-IMRT) for patients with early-stage Hodgkin’s lymphoma (HL) with mediastinal involvement. Fifty-two patients with early-stage HL that involved the mediastinum were reviewed. Eight patients had Stage I disease, and 44 patients had Stage II disease. Twenty-three patients (44%) presented with a bulky mediastinum, whereas 42 patients (81%) had involvement of both the mediastinum and either cervical or axillary nodes. All patients received combination chemotherapy followed by IF-IMRT. The prescribed radiation dose was 30–40 Gy. The dose–volume histograms of the target volume and critical normal structures were evaluated. The median mean dose to the primary involved regions (planning target volume, PTV1) and boost area (PTV2) was 37.5 Gy and 42.1 Gy, respectively. Only 0.4% and 1.3% of the PTV1 and 0.1% and 0.5% of the PTV2 received less than 90% and 95% of the prescribed dose, ...


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

Mené sur 119 patients atteints d'un cancer colorectal avec métastases hépatiques non résécables, cet essai randomisé de phase II évalue, du point de vue de la survie sans progression et de la survie globale à 30 mois, l'intérêt de combiner un traitement systémique à une ablation de métastases par radiofréquences

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    Mené sur 119 patients atteints d'un cancer colorectal avec métastases hépatiques non résécables, cet essai randomisé de phase II évalue, du point de vue de la survie sans progression et de la survie globale à 30 mois, l'intérêt de combiner un traitement systémique à une ablation de métastases par radiofréquences

    “Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004)”

    • Ruers, T.;Punt, C.;Van Coevorden, F.;Pierie, J. P. E. N.;Borel-Rinkes, I.;Ledermann, J. A.;Poston, G.;Bechstein, W.;Lentz, M. A.;Mauer, M.;Van Cutsem, E.;Lutz, M. P.;Nordlinger, B.

    Background: This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases.Methods: This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA (±resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group.Results: The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2–73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1–70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42–0.95, P = 0.025). Median progression-free ...


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

Ressources et infrastructures (Traitements)

Cet article passe en revue les essais cliniques qui ont servi de base à l'autorité réglementaire américaine pour autoriser la mise sur le marche de traitements du cancer du sein métastatique au cours des deux dernières décennies

  • US Food and Drug Administration Approval Overview in Metastatic Breast Cancer
    Journal of Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les essais cliniques qui ont servi de base à l'autorité réglementaire américaine pour autoriser la mise sur le marche de traitements du cancer du sein métastatique au cours des deux dernières décennies

    “US Food and Drug Administration Approval Overview in Metastatic Breast Cancer”

    • Cortazar, Patricia;Justice, Robert;Johnson, John;Sridhara, Rajeshwari;Keegan, Patricia;Pazdur, Richard

    We reviewed trials that supported US Food and Drug Administration (FDA) approvals of drugs and biologics for the treatment of metastatic breast cancer (MBC) in the last two decades. This summary provides an overview of the basis for approval, including end points, trial design, major trial findings, and regulatory considerations. Approval of hormonal agents is excluded from this analysis. In the last two decades, 10 products with 14 MBC indications (four for first-line and 10 for second- to third-line treatment) were approved by the FDA. Approval decisions for these 14 indications were supported by a variety of end points that showed a favorable benefit-to-risk profile. Among these 14 indications, four were granted accelerated approval (AA), and 10 were given regular approval (RA). Of the four approved under AA, two have subsequently demonstrated clinical benefit resulting in conversion to RA. We conclude with current FDA thinking on the drug development challenges for the treatment ...


Mots clés : Sein; Traitements (Ressources et infrastructures (Traitements))

Cet article présente une nouvelle approche faisant appel à la biologie des systèmes et à la pharmacodynamique pour faciliter le développement de traitements personnalisés

  • Merging Systems Biology with Pharmacodynamics
    Science Translational Medicine, Vol. 4 (126), pp. 126ps7, 2012 (résumé)
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    Cet article présente une nouvelle approche faisant appel à la biologie des systèmes et à la pharmacodynamique pour faciliter le développement de traitements personnalisés

    “Merging Systems Biology with Pharmacodynamics”

    • Iyengar, Ravi;Zhao, Shan;Chung, Seung-Wook;Mager, Donald E.;Gallo, James M.

    The emerging discipline of systems pharmacology aims to combine analysis and computational modeling of cellular regulatory networks with quantitative pharmacology approaches to drive the drug discovery processes, predict rare adverse events, and catalyze the practice of personalized precision medicine. Here, we introduce the concept of enhanced pharmacodynamic (ePD) models, which synergistically combine the desirable features of systems biology and current PD models within the framework of ordinary or partial differential equations. ePD models that analyze regulatory networks involved in drug action can account for a drug’s multiple targets and for the effects of genomic, epigenomic, and posttranslational changes on the drug efficacy. This new knowledge can drive drug discovery and shape precision medicine.


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

Menée par entretiens auprès de 26 patients britanniques invités à participer à un essai clinique, cette étude évalue leur degré de compréhension du document d'information qui leur est remis

  • Détails
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    Menée par entretiens auprès de 26 patients britanniques invités à participer à un essai clinique, cette étude évalue leur degré de compréhension du document d'information qui leur est remis

    “Do informed consent documents for cancer trials do what they should? A study of manifest and latent functions”

    • Armstrong, Natalie;Dixon-Woods, Mary;Thomas, Anne;Rusk, Gill;Tarrant, Carolyn

    Though patient information leaflets (PILs) are provided to those invited to take part in medical research, they usually fall short in facilitating informed decisions about participation. We aimed to explore why there is an enduring requirement for a process that seems not to ‘work’, and to explain why the problems have proven resistant to correction. We analysed applications for ethical approval for 13 oncology trials and related official guidance. We interviewed 26 patients invited to participate in the trials. Data analysis was based on the constant comparative method. We show that PILs function latently to satisfy purposes other than their manifest function as a decision-facilitating tool. PILs are the outcome of a process of institutional scripting that is strongly shaped by the accountability demands inherent in the ethical review process. This results in the PIL being made to serve purposes both as a prospectus and as a contract. Though PILs have value for some patients, ...


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

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