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Accueil Nota Bene Cancer V2 Numéro 135 du 10 May 2012 Traitements

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Nota Bene Cancer Numéro 135 du 10 May 2012 RSS

Traitements

Traitements localisés : découverte et développement

Mené sur 29 patients atteints d'un cancer des glandes salivaires, cet essai prospectif de phase II évalue, selon la présence et la gravité de mucites post-traitement, la toxicité d'une radiothérapie avec modulation d'intensité combinée à une irradiation additionnelle du lit tumoral par ions carbone

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    Mené sur 29 patients atteints d'un cancer des glandes salivaires, cet essai prospectif de phase II évalue, selon la présence et la gravité de mucites post-traitement, la toxicité d'une radiothérapie avec modulation d'intensité combinée à une irradiation additionnelle du lit tumoral par ions carbone

    “IMRT and carbon ion boost for malignant salivary gland tumors : interim analysis of the COSMIC trial”

    • Jensen, Alexandra;Nikoghosyan, Anna;Lossner, Karen;Herfarth, Klaus;Debus, Jurgen;Munter, Marc

    Purpose To evaluate toxicity in dose-escalated treatment with intensity-modulated radiotherapy (IMRT) and carbon ion boost for malignant salivary gland tumors (MSGT) of the head and neck including patients with inoperable/ incompletely resected MSGTs (R2-group) and completely resected tumors plus involved margins or perineural spread (R1-group).METHODS:COSMIC is a prospective phase II trial of IMRT (25 x 2 Gy) and carbon ion boost (8 x 3 GyE). Primary endpoint is mucositis CTCdegreesIII, secondary endpoints are local control, progression-free survival, and toxicity. Evaluation of disease response is carried out according to the Response Evaluation Criteria in Solid Tumors (RECIST); toxicity is assessed using NCI CTC v 3.0.RESULTS:Twenty-nine patients were recruited from 07/2010 to 04/2011, all patients have at least completed first follow-up. Sixteen patients were treated in the R2-group, 13 in the R1-group. All treatments were completed as planned and well tolerated, mucositis CTC ...


Mots clés : Voies aérodigestives supérieures; Traitements (Traitements localisés : découverte et développement)

Traitements localisés : applications cliniques

Menée sur 195 patients atteints d'un carcinome métastatique à cellules rénales et ayant subi une néphrectomie radicale entre 1989 et 2009, cette étude monocentrique caractérise les complications post-opératoires et identifie les facteurs prédictifs associés

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    Menée sur 195 patients atteints d'un carcinome métastatique à cellules rénales et ayant subi une néphrectomie radicale entre 1989 et 2009, cette étude monocentrique caractérise les complications post-opératoires et identifie les facteurs prédictifs associés

    “Systematic classification and prediction of complications after nephrectomy in patients with metastatic renal cell carcinoma (RCC)”

    • Silberstein, Jonathan L.;Adamy, Ari;Maschino, Alexandra C.;Ehdaie, Behfar;Garg, Tullika;Favaretto, Ricardo L.;Ghoneim, Tarek P.;Motzer, Robert J.;Russo, Paul

    Study Type – Harm (case series)Level of Evidence  4What's known on the subject? and What does the study add?Radical nephrectomy for patients with metastatic renal cell carcinoma results in greater rates of morbidity than for those with less advanced disease.This study systematically characterizes complications associated with nephrectomy for metastatic RCC and identifies patient and disease characteristics that are associated with a greater risk of developing complications. Overall complications were relatively frequent, but major complications (grade 3 or greater) were rare. Increasing age and worsening performance status were associated with increased probability of complications. When complications were sustained, patients were less likely to receive systemic therapy in a timely fashion. These observations may influence the timing or patient selection for surgery or systemic therapy. OBJECTIVE * •To evaluate and identify factors predictive for morbidity after radical ...


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

Mené sur 250 patients atteints d'un mélanome et ayant subi une lymphadénectomie (durée médiane de suivi : 40 mois), cet essai multicentrique international (Australie, Nouvelle-Zélande, Pays-Bas, Brésil) évalue l'intérêt d'une radiothérapie adjuvante pour diminuer le risque de métastases ganglionnaires

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    Mené sur 250 patients atteints d'un mélanome et ayant subi une lymphadénectomie (durée médiane de suivi : 40 mois), cet essai multicentrique international (Australie, Nouvelle-Zélande, Pays-Bas, Brésil) évalue l'intérêt d'une radiothérapie adjuvante pour diminuer le risque de métastases ganglionnaires

    “Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial”

    • Burmeister, Bryan H.;Henderson, Michael A.;Ainslie, Jill;Fisher, Richard;Di Iulio, Juliana;Smithers, B. Mark;Hong, Angela;Shannon, Kerwin;Scolyer, Richard A.;Carruthers, Scott;Coventry, Brendon J.;Babington, Scott;Duprat, Joao;Hoekstra, Harald J.;Thompson, John F.

    The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, ...


  • Finally, a substantial role for radiotherapy in melanoma
    The Lancet Oncology, sous presse, 2012 (commentaire)
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    Mené sur 250 patients atteints d'un mélanome et ayant subi une lymphadénectomie (durée médiane de suivi : 40 mois), cet essai multicentrique international (Australie, Nouvelle-Zélande, Pays-Bas, Brésil) évalue l'intérêt d'une radiothérapie adjuvante pour diminuer le risque de métastases ganglionnaires

    “Finally, a substantial role for radiotherapy in melanoma”

    • Macklis, Roger


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

Cette étude compare, du point de vue de la survie sans récidive à 5 ans, l'efficacité d'une greffe allogénique de cellules souches hématopoïétiques et de traitements alternatifs pour réduire le risque de récidive chez les patients atteints d'une leucémie myéloïde aiguë avec ou sans monosomie (2 560 patients ; 305 cas ; âge : inférieur à 61 ans)

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    Cette étude compare, du point de vue de la survie sans récidive à 5 ans, l'efficacité d'une greffe allogénique de cellules souches hématopoïétiques et de traitements alternatifs pour réduire le risque de récidive chez les patients atteints d'une leucémie myéloïde aiguë avec ou sans monosomie (2 560 patients ; 305 cas ; âge : inférieur à 61 ans)

    “Comparative Analysis of the Value of Allogeneic Hematopoietic Stem-Cell Transplantation in Acute Myeloid Leukemia With Monosomal Karyotype Versus Other Cytogenetic Risk Categories”

    • Cornelissen, Jan J.;Breems, Dimitri;van Putten, Wim L.J.;Gratwohl, Alois A.;Passweg, Jakob R.;Pabst, Thomas;Maertens, Johan;Beverloo, H. Berna;van Marwijk Kooy, Marinus;Wijermans, Pierre W.;Biemond, Bart J.;Vellenga, Edo;Verdonck, Leo F.;Ossenkoppele, Gert J.;Löwenberg, Bob

    Purpose To determine to what extent allogeneic hematopoietic stem-cell transplantation (alloHSCT) quantitatively reduces relapse in acute myeloid leukemia with monosomal karyotype (MK-AML) compared with alternative postremission therapy and how it compares with other cytogenetic subcategories.Patients and Methods Of 2,560 patients (younger than age 61 years) without core-binding factor abnormalities including 305 patients with MK-AML receiving first-line induction treatment, 1,975 patients (77%) achieved remission, and 1,588 received consolidation in the first complete remission (CR1) after two induction cycles. Consolidation treatment of 107 patients with MK-AML consisted of alloHSCT (n = 45), chemotherapy (n = 48), or autologous HSCT (n = 14).Results The 5-year overall survival after start of consolidation was 19% for patients with MK-AML who received alloHSCT and 9% for those who received chemotherapy or autoHSCT (P = .02). Relapse-free survival (RFS) at 5 years was 17% versus 7% ...


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

Traitements systémiques : découverte et développement

Menée in vitro et à l'aide de xénogreffes, cette étude suggère l'intérêt d'une immunothérapie adoptive à l'aide de cellules NKT surexprimant l'interleukine 15 pour le traitement des neuroblastomes

  • IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Menée in vitro et à l'aide de xénogreffes, cette étude suggère l'intérêt d'une immunothérapie adoptive à l'aide de cellules NKT surexprimant l'interleukine 15 pour le traitement des neuroblastomes

    “IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity”

    • Liu, Daofeng;Song, Liping;Wei, Jie;Courtney, Amy N.;Gao, Xiuhua;Marinova, Ekaterina;Guo, Linjie;Heczey, Andras;Asgharzadeh, Shahab;Kim, Eugene;Dotti, Gianpietro;Metelitsa, Leonid S.

    Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and ...


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

Mené sur 16 patients atteints d'un cancer localisé de la prostate (âge médian : 63 ans), cet essai de phase II évalue le figitumumab, un anticorps monoclonal anti IGF-IR

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    Mené sur 16 patients atteints d'un cancer localisé de la prostate (âge médian : 63 ans), cet essai de phase II évalue le figitumumab, un anticorps monoclonal anti IGF-IR

    “A Phase 2 Pharmacodynamic Study of Pre-operative Figitumumab in Patients with Localized Prostate Cancer”

    • Chi, Kim N.;Gleave, Martin E;Fazli, Ladan;Goldenberg, S Larry;So, Alan;Kollmannsberger, Christian;Murray, Nevin;Tinker, Anna V;Pollak, Michael N.

    Purpose: Activation of the insulin-like growth factor 1 receptor (IGF-IR) is implicated in prostate cancer development and progression. This study evaluated biologic and clinical effects of figitumumab, a fully human monoclonal IGF-IR antibody, in patients with localized prostate cancer. Patients and Methods: Eligible patients received figitumumab 20 mg/kg intravenously every 3 weeks for 3 cycles followed by prostatectomy. The primary endpoint was IGF-IR expression inhibition as assessed by immunohistochemistry. Results: Sixteen patients were accrued. Median age was 63 years, median PSA was 7.2 mu g/L (range 2.5-35), clinical stage was T1 in 4 patients and T2 in 12 patients, Gleason score (less than or equal to)7 or greater than 7 in 15 and 1 patients. Two patients received only 1 cycle (patient choice and grade 3 hyperglycemia). A PSA decline from baseline of (greater than or equal to)25% and (greater than or equal to)50% occurred in 15 (94%) and 5 (31%) of patients. Mean figitumumab ...


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

Menée in vitro et à l'aide de xénogreffes, cette étude évalue les effets d'un antagoniste du récepteur Smoothened de la voie de signalisation Hedgehog sur la réponse à une chimiothérapie à base de taxanes dans le cancer de l'ovaire

  • Smoothened Antagonists Reverse Taxane Resistance in Ovarian Cancer
    Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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    Menée in vitro et à l'aide de xénogreffes, cette étude évalue les effets d'un antagoniste du récepteur Smoothened de la voie de signalisation Hedgehog sur la réponse à une chimiothérapie à base de taxanes dans le cancer de l'ovaire

    “Smoothened Antagonists Reverse Taxane Resistance in Ovarian Cancer”

    • Steg, Adam D.;Katre, Ashwini A.;Bevis, Kerri S.;Ziebarth, Angela;Dobbin, Zachary C.;Shah, Monjri M.;Alvarez, Ronald D.;Landen, Charles N.

    The hedgehog (HH) pathway has been implicated in the formation and maintenance of a variety of malignancies, including ovarian cancer; however, it is unknown whether HH signaling is involved in ovarian cancer chemoresistance. The goal of this study was to determine the effects of antagonizing the HH receptor, Smoothened (Smo), on chemotherapy response in ovarian cancer. Expression of HH pathway members was assessed in 3 pairs of parental and chemotherapy-resistant ovarian cancer cell lines (A2780ip2/A2780cp20, SKOV3ip1/SKOV3TRip2, HeyA8/HeyA8MDR) using qPCR and Western blot. Cell lines were exposed to increasing concentrations of two different Smo antagonists (cyclopamine, LDE225) alone and in combination with carboplatin or paclitaxel. Selective knockdown of Smo, Gli1 or Gli2 was achieved using siRNA constructs. Cell viability was assessed by MTT assay. A2780cp20 and SKOV3TRip2 orthotopic xenografts were treated with vehicle, LDE225, paclitaxel or combination therapy. Chemoresistant ...


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

Mené sur des cellules isolées à partir d'échantillons prélevés sur des patientes atteintes d'un cancer avancé de l'ovaire, cette étude évalue l'association entre des anomalies relatives à la voie de signalisation PI3K et la résistance thérapeutique

  • The association of PI3 kinase signalling and chemo-resistance in advanced ovarian cancer
    Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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    Mené sur des cellules isolées à partir d'échantillons prélevés sur des patientes atteintes d'un cancer avancé de l'ovaire, cette étude évalue l'association entre des anomalies relatives à la voie de signalisation PI3K et la résistance thérapeutique

    “The association of PI3 kinase signalling and chemo-resistance in advanced ovarian cancer”

    • Carden, Craig P;Stewart, Adam;Thavasu, Parames;Kipps, Emma;Pope, Lorna;Crespo, Mateus;Miranda, Susana;Attard, Gerhardt;Garrett, Michelle D;Clarke, Paul A;Workman, Paul;de Bono, Johann S.;Gore, Martin;Kaye, Stan B;Banerji, Udai

    Evidence that the phosphatidylinositide-3-kinase (PI3K) pathway is deregulated in ovarian cancer is largely based on analysis of surgical specimens sampled at diagnosis and may not reflect the biology of advanced ovarian cancer. We aimed to investigate PI3K signalling in cancer cells isolated from patients with advanced ovarian cancer. Ascites samples were analysed from 88 patients, of whom 61 received further treatment. Cancer cells were immunomagnetically separated from ascites and the signalling output of the PI3K pathway was studied by quantifying p-AKT, p-p70S6K and p-GSK3β by ELISA. Relevant oncogenes such as PIK3CA and AKT were sequenced by PCR-amplified mass spectroscopy detection methods. In addition, PIK3CA and AKT2 amplifications and PTEN deletions were analysed by fluorescent-in-situ hybridization. p-p70S6K levels were significantly higher in cells from 37/61 patients who did not respond to subsequent chemotherapy (0.7184 vs 0.3496; p = 0.0100) and this difference was ...


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

Mené sur 129 patients atteints d'un myélome multiple récidivant et/ou réfractaire non exposés au bortezomib, cet essai de phase II évalue, du point de vue du taux de réponse globale, le carfilzomib, un inhibiteur sélectif du protéasome

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    Mené sur 129 patients atteints d'un myélome multiple récidivant et/ou réfractaire non exposés au bortezomib, cet essai de phase II évalue, du point de vue du taux de réponse globale, le carfilzomib, un inhibiteur sélectif du protéasome

    “An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naïve patients with relapsed and/or refractory multiple myeloma”

    • Vij, Ravi;Wang, Michael;Kaufman, Jonathan L.;Lonial, Sagar;Jakubowiak, Andrzej J.;Stewart, A. Keith;Kukreti, Vishal;Jagannath, Sundar;McDonagh, Kevin T.;Alsina, Melissa;Bahlis, Nizar J.;Reu, Frederic J.;Gabrail, Nashat Y.;Belch, Andrew;Matous, Jeffrey V.;Lee, Peter;Rosen, Peter;Sebag, Michael;Vesole, David H.;Kunkel, Lori A.;Wear, Sandra M.;Wong, Alvin F.;Orlowski, Robert Z.;Siegel, David S.

    Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In this phase 2 multicenter, open-label study, 129 bortezomib-naïve patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous (IV) carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for Cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary endpoint was overall response rate (ORR, ≥ partial response): 42.4% in Cohort 1 and 52.2% in Cohort 2. Clinical benefit response (ORR + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events ...


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

Mené sur 19 patients atteints d'une leucémie myéloïde aiguë (âge médian : 70 ans), cet essai de phase I évalue la toxicité et l'activité clinique d'un traitement combinant decitabine et bortezomib

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    Mené sur 19 patients atteints d'une leucémie myéloïde aiguë (âge médian : 70 ans), cet essai de phase I évalue la toxicité et l'activité clinique d'un traitement combinant decitabine et bortezomib

    “Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia”

    • Blum, William;Schwind, Sebastian;Tarighat, Somayeh S.;Geyer, Susan;Eisfeld, Ann-Kathrin;Whitman, Susan;Walker, Alison;Klisovic, Rebecca;Byrd, John C.;Santhanam, Ramasamy;Wang, Hongyan;Curfman, John P.;Devine, Steven M.;Jacob, Samson;Garr, Celia;Kefauver, Cheryl;Perrotti, Danilo;Chan, Kenneth K.;Bloomfield, Clara D.;Caligiuri, Michael A.;Grever, Michael R.;Garzon, Ramiro;Marcucci, Guido

    We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b upregulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis including DNA methyltransferases (DNMTs) and receptor tyrosine kinases (RTKs). Thus, a phase I trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84) enrolled. Induction with decitabine (20mg/m2 IV on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m2 on days 5, 8, 12, and 15) was tolerable, but bortezomib-related neuropathy developed after repetitive cycles. Of previously untreated patients (age>65), 5/10 had CR (complete remission, N=4) or incomplete CR (CRi, N=1); 7/19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 downregulation ...


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

Mené sur 38 patients atteints d'un cancer colorectal métastatique, cet essai de phase I évalue la toxicité et l'activité antitumorale du regorafenib

  • Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study
    British Journal of Cancer, sous presse, 2012 (résumé)
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    Mené sur 38 patients atteints d'un cancer colorectal métastatique, cet essai de phase I évalue la toxicité et l'activité antitumorale du regorafenib

    “Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study”

    • Strumberg, D.;Scheulen, M. E.;Schultheis, B.;Richly, H.;Frost, A.;Buchert, M.;Christensen, O.;Jeffers, M.;Heinig, R.;Boix, O.;Mross, K.

    Background: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). Methods: Patients received oral regorafenib 60–220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. Results: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% ...


Mots clés : Colon-rectum; Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par l'usage de cannabinoïdes pour le traitement des cancers

  • Towards the use of cannabinoids as antitumour agents
    Nature Reviews Cancer, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par l'usage de cannabinoïdes pour le traitement des cancers

    “Towards the use of cannabinoids as antitumour agents”

    • Velasco, Guillermo;Sánchez, Cristina;Guzmán, Manuel

    Various reports have shown that cannabinoids (the active components of marijuana and their derivatives) can reduce tumour growth and progression in animal models of cancer, in addition to their well-known palliative effects on some cancer-associated symptoms. This Opinion article discusses our current understanding of cannabinoids as antitumour agents, focusing on recent insights into the molecular mechanisms of action, including emerging resistance mechanisms and opportunities for combination therapy approaches. Such knowledge is required for the optimization of preclinical cannabinoid-based therapies and for the preliminary clinical testing that is currently underway.


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

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme de rétroaction par lequel un inhibiteur de MEK induit l'activation de la voie de signalisation PI3K/AKT

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    Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme de rétroaction par lequel un inhibiteur de MEK induit l'activation de la voie de signalisation PI3K/AKT

    “MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors”

    • Turke, Alexa B.;Song, Youngchul;Costa, Carlotta;Cook, Rebecca;Arteaga, Carlos L.;Asara, John M;Engelman, Jeffrey A.

    The PI3K/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-agent targeted therapies. In this study we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found that MEK inhibitor-induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane (JM) domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and up-regulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK ...


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

Mené sur 110 patients atteints de tumeurs solides de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé RO4929097, un inhibiteur de la gamma secrétase

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    Mené sur 110 patients atteints de tumeurs solides de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé RO4929097, un inhibiteur de la gamma secrétase

    “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 ...


  • Moving Forward One Notch at a Time
    Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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    Mené sur 110 patients atteints de tumeurs solides de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé RO4929097, un inhibiteur de la gamma secrétase

    “Moving Forward One Notch at a Time”

    • Gounder, Mrinal M. ; Schwartz, Gary K.


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

Menée in vitro, cette étude met en évidence un mécanisme de régulation de la traduction de l'ARN messager par un inhibiteur de mTOR, Torin 1

  • A unifying model for mTORC1-mediated regulation of mRNA translation
    Nature, Vol. 485 (7396), pp. 109-113, 2012 (résumé)
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    Menée in vitro, cette étude met en évidence un mécanisme de régulation de la traduction de l'ARN messager par un inhibiteur de mTOR, Torin 1

    “A unifying model for mTORC1-mediated regulation of mRNA translation”

    • Thoreen, Carson C.;Chantranupong, Lynne;Keys, Heather R.;Wang, Tim;Gray, Nathanael S.;Sabatini, David M.

    The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5′ terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no ...


  • Cancer biology: The director's cut
    Nature, Vol. 485 (7396), pp. 50-51, 2012 (commentaire)
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    Menée in vitro, cette étude met en évidence un mécanisme de régulation de la traduction de l'ARN messager par un inhibiteur de mTOR, Torin 1

    “Cancer biology: The director's cut”

    • Gentilella, Antonio ; Thomas, George

    A genome-wide characterization of active translation of messenger RNA following inhibition of mTOR will transform our view of this signalling protein's regulatory role in cancer.


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

Cet article passe en revue les perspectives offertes par le développement d'inhibiteurs de MET, et de biomarqueurs prédictifs associés, pour le traitement des cancers

  • MET: a promising anticancer therapeutic target
    Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par le développement d'inhibiteurs de MET, et de biomarqueurs prédictifs associés, pour le traitement des cancers

    “MET: a promising anticancer therapeutic target”

    • Peters, Solange;Adjei, Alex A.

    The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors—including identification of predictive biomarkers—as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.


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

Menée sur un modèle murin, cette étude évalue l'activité antitumorale d'un composé appelé Lys01, un inhibiteur de l'autophagie

  • Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée sur un modèle murin, cette étude évalue l'activité antitumorale d'un composé appelé Lys01, un inhibiteur de l'autophagie

    “Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency”

    • McAfee, Quentin;Zhang, Zhihui;Samanta, Arabinda;Levi, Samuel M.;Ma, Xiao-Hong;Piao, Shengfu;Lynch, John P.;Uehara, Takeshi;Sepulveda, Antonia R.;Davis, Lisa E.;Winkler, Jeffrey D.;Amaravadi, Ravi K.

    Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the ...


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

Menée in vitro et in vivo, cette étude évalue l'intérêt de nouveaux composés appelés ImmTACs pour l'immunothérapie des cancers

  • Monoclonal TCR-redirected tumor cell killing
    Nature Medicine, sous presse, 2012 (résumé)
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    Menée in vitro et in vivo, cette étude évalue l'intérêt de nouveaux composés appelés ImmTACs pour l'immunothérapie des cancers

    “Monoclonal TCR-redirected tumor cell killing”

    • Liddy, Nathaniel;Bossi, Giovanna;Adams, Katherine J.;Lissina, Anna;Mahon, Tara M.;Hassan, Namir J.;Gavarret, Jessie;Bianchi, Frayne C.;Pumphrey, Nicholas J.;Ladell, Kristin;Gostick, Emma;Sewell, Andrew K.;Lissin, Nikolai M.;Harwood, Naomi E.;Molloy, Peter E.;Li, Yi;Cameron, Brian J.;Sami, Malkit;Baston, Emma E.;Todorov, Penio T.;Paston, Samantha J.;Dennis, Rebecca E.;Harper, Jane V.;Dunn, Steve M.;Ashfield, Rebecca;Johnson, Andy;McGrath, Yvonne;Plesa, Gabriela;June, Carl H.;Kalos, Michael;Price, David A.;Vuidepot, Annelise;Williams, Daniel D.;Sutton, Deborah H.;Jakobsen, Bent K.

    T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.


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

Menée in vitro et in vivo, cette étude évalue la faisabilité d'utiliser des salmonelles se fixant spécifiquement sur les tumeurs pour développer des traitements du cancer

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    Menée in vitro et in vivo, cette étude évalue la faisabilité d'utiliser des salmonelles se fixant spécifiquement sur les tumeurs pour développer des traitements du cancer

    “A Bioluminescent Transposon Reporter-Trap Identifies Tumor-Specific Microenvironment-Induced Promoters in Salmonella for Conditional Bacterial-Based Tumor Therapy”

    • Flentie, Kelly;Kocher, Brandon;Gammon, Seth T;Novack, Deborah Veis;McKinney, Jeffrey S;Piwnica-Worms, David

    Salmonella specifically localize to malignant tumors in vivo, a trait potentially exploitable as a delivery system for cancer therapeutics. To characterize mechanisms and genetic responses of Salmonella during interaction with living neoplastic cells, we custom designed a promoterless transposon reporter containing bacterial luciferase. Analysis of a library containing 7,400 independent Salmonella transposon insertion mutants in co-culture with melanoma or colon carcinoma cells identified five bacterial genes specifically activated by cancer cells: adiY, yohJ, STM1787, STM1791, and STM1793. Experiments linked acidic pH, a common characteristic of the tumor microenvironment, to a strong, specific and reversible stimulus for activation of these Salmonella genes in vitro and in vivo. Indeed, a Salmonella reporter strain encoding a luciferase transgene regulated by the STM1787 promoter, which contains a tusp motif, showed tumor-induced bioluminescence in vivo. Furthermore, Salmonella ...


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

Traitements systémiques : applications cliniques

Mené sur 200 patientes non diabétiques atteintes d'un cancer du sein opérable, cet essai évalue, du point de vue du dosage du marqueur de prolifération Ki67, l'intérêt d'un traitement pré-opératoire à base de metformine

  • Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial
    Journal of Clinical Oncology, sous presse, 2012 (résumé)
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    Mené sur 200 patientes non diabétiques atteintes d'un cancer du sein opérable, cet essai évalue, du point de vue du dosage du marqueur de prolifération Ki67, l'intérêt d'un traitement pré-opératoire à base de metformine

    “Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial”

    • Bonanni, Bernardo;Puntoni, Matteo;Cazzaniga, Massimiliano;Pruneri, Giancarlo;Serrano, Davide;Guerrieri-Gonzaga, Aliana;Gennari, Alessandra;Stella Trabacca, Maria;Galimberti, Viviana;Veronesi, Paolo;Johansson, Harriet;Aristarco, Valentina;Bassi, Fabio;Luini, Alberto;Lazzeroni, Matteo;Varricchio, Clara;Viale, Giuseppe;Bruzzi, Paolo;DeCensi, Andrea

    Purpose Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.Patients and methods After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.Results Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, −5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] × insulin [mU/L]/22.5; ...


  • Cracking Open Window of Opportunity Trials
    Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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    Mené sur 200 patientes non diabétiques atteintes d'un cancer du sein opérable, cet essai évalue, du point de vue du dosage du marqueur de prolifération Ki67, l'intérêt d'un traitement pré-opératoire à base de metformine

    “Cracking Open Window of Opportunity Trials”

    • Kalinsky, Kevin ; Hershman, Dawn L.


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

Mené sur 111 patientes atteintes d'un cancer métastatique du sein résistant aux inhibiteurs d'aromatase, cet essai français de phase II évalue la toxicité et l'efficacité de l'évérolimus en combinaison avec du tamoxifène

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    Mené sur 111 patientes atteintes d'un cancer métastatique du sein résistant aux inhibiteurs d'aromatase, cet essai français de phase II évalue la toxicité et l'efficacité de l'évérolimus en combinaison avec du tamoxifène

    “Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study”

    • Bachelot, Thomas;Bourgier, Céline;Cropet, Claire;Ray-Coquard, Isabelle;Ferrero, Jean-Marc;Freyer, Gilles;Abadie-Lacourtoisie, Sophie;Eymard, Jean-Christophe;Debled, Marc;Spaëth, Dominique;Legouffe, Eric;Allouache, Djelila;El Kouri, Claude;Pujade-Lauraine, Eric

    Purpose Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs).Patients and Methods This open-label, phase II study randomly assigned postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No ...


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

Mené sur 246 patients atteints d'un ostéosarcome non métastatique des extrêmités, cet essai italien évalue l'ajout d'ifosfamide à une chimiothérapie néoadjuvante combinant méthotrexate, cisplatine et doxorubicine

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    Mené sur 246 patients atteints d'un ostéosarcome non métastatique des extrêmités, cet essai italien évalue l'ajout d'ifosfamide à une chimiothérapie néoadjuvante combinant méthotrexate, cisplatine et doxorubicine

    “Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1”

    • Ferrari, Stefano;Ruggieri, Pietro;Cefalo, Graziella;Tamburini, Angela;Capanna, Rodolfo;Fagioli, Franca;Comandone, Alessandro;Bertulli, Rossella;Bisogno, Gianni;Palmerini, Emanuela;Alberghini, Marco;Parafioriti, Antonina;Linari, Alessandra;Picci, Piero;Bacci, Gaetano

    Purpose We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity.Patients and Methods Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m2, MTX 120 g/m2, CDP 600 mg/m2, and IFO 30 g/m2) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS).Results From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; ...


  • Ifosfamide in the Neoadjuvant Treatment of Osteogenic Sarcoma
    Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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    Mené sur 246 patients atteints d'un ostéosarcome non métastatique des extrêmités, cet essai italien évalue l'ajout d'ifosfamide à une chimiothérapie néoadjuvante combinant méthotrexate, cisplatine et doxorubicine

    “Ifosfamide in the Neoadjuvant Treatment of Osteogenic Sarcoma”

    • Maki, Robert G.


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

Mené sur 960 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue, du point de vue de la survie globale, l'ajout de sunitinib à l'erlotinib

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    Mené sur 960 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue, du point de vue de la survie globale, l'ajout de sunitinib à l'erlotinib

    “Sunitinib Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer: A Phase III Trial”

    • Scagliotti, Giorgio V.;Krzakowski, Maciej;Szczesna, Aleksandra;Strausz, Janos;Makhson, Anatoly;Reck, Martin;Wierzbicki, Rafal F.;Albert, Istvan;Thomas, Michael;Miziara, Jose Elias Abrao;Papai, Zsolt S.;Karaseva, Nina;Thongprasert, Sumitra;Dalmau Portulas, Elsa;von Pawel, Joachim;Zhang, Ke;Selaru, Paulina;Tye, Lesley;Chao, Richard C.;Govindan, Ramaswamy

    Purpose Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non–small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC.Patients and Methods Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.Results In all, 960 patients were randomly assigned, and ...


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

Cet article analyse les travaux récents sur le traitement des mélanomes présentant la mutation BRAFV600E

  • The role of BRAF V600 mutation in melanoma
    Journal of Translational Medicine, Vol. 10 (1), pp. 85, 2012 (article en libre accès)
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    Cet article analyse les travaux récents sur le traitement des mélanomes présentant la mutation BRAFV600E

    “The role of BRAF V600 mutation in melanoma”

    • Ascierto, Paolo;Kirkwood, John;Grob, Jean-Jacques;Simeone, Ester;Grimaldi, Antonio;Maio, Michele;Palmieri, Giuseppe;Testori, Alessandro;Marincola, Francesco;Mozzillo, Nicola

    BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50% of melanomas harbors activating BRAF mutations (over 90% V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naive patients (BRIM-3). The study results showed a relative reduction of 63% in risk of death and 74% in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas ...


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

Mené sur 304 patients atteints d'un carcinome adrénocortical de stade avancé, cet essai suédois évalue, du point de vue de la survie globale, le mitotane en combinaison avec la streptozotocine ou un protocole à base d'étoposide, de doxorubicine et de cisplatine

  • Combination Chemotherapy in Advanced Adrenocortical Carcinoma
    New England Journal of Medicine, sous presse, 2012 (article en libre accès)
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    Mené sur 304 patients atteints d'un carcinome adrénocortical de stade avancé, cet essai suédois évalue, du point de vue de la survie globale, le mitotane en combinaison avec la streptozotocine ou un protocole à base d'étoposide, de doxorubicine et de cisplatine

    “Combination Chemotherapy in Advanced Adrenocortical Carcinoma”

    • Fassnacht, Martin;Terzolo, Massimo;Allolio, Bruno;Baudin, Eric;Haak, Harm;Berruti, Alfredo;Welin, Staffan;Schade-Brittinger, Carmen;Lacroix, André;Jarzab, Barbara;Sorbye, Halfdan;Torpy, David J.;Stepan, Vinzenz;Schteingart, David E.;Arlt, Wiebke;Kroiss, Matthias;Leboulleux, Sophie;Sperone, Paola;Sundin, Anders;Hermsen, Ilse;Hahner, Stefanie;Willenberg, Holger S.;Tabarin, Antoine;Quinkler, Marcus;de la Fouchardière, Christelle;Schlumberger, Martin;Mantero, Franco;Weismann, Dirk;Beuschlein, Felix;Gelderblom, Hans;Wilmink, Hanneke;Sender, Monica;Edgerly, Maureen;Kenn, Werner;Fojo, Tito;Müller, Hans-Helge;Skogseid, Britt

    Background: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. Methods: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. Results: For first-line therapy, patients in the EDP–mitotane group had a significantly higher response rate than those in the streptozocin–mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; ...


Mots clés : Glande endocrine (autre); Traitements (Traitements systémiques : applications cliniques)

Combinaison de traitements localisés et systémiques

Menée sur 150 patients atteints d'un cancer localement avancé de la tête et du cou (durée médiane de suivi : 30 mois), cette étude rétrospective évalue, du point de vue du contrôle locorégional de la maladie et de la survie globale, la toxicité et l'efficacité d'une radiothérapie avec modulation d'intensité combinée à une chimiothérapie concomitante par carboplatine et paclitaxel

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    Menée sur 150 patients atteints d'un cancer localement avancé de la tête et du cou (durée médiane de suivi : 30 mois), cette étude rétrospective évalue, du point de vue du contrôle locorégional de la maladie et de la survie globale, la toxicité et l'efficacité d'une radiothérapie avec modulation d'intensité combinée à une chimiothérapie concomitante par carboplatine et paclitaxel

    “Intensity-Modulated Radiation Therapy with Concurrent Carboplatin and Paclitaxel for Locally Advanced Head and Neck Cancer: Toxicities and Efficacy”

    • Vlacich, Gregory;Diaz, Roberto;Thorpe, Steven W.;Murphy, Barbara A.;Kirby, Wyndee;Sinard, Robert J.;Shakhtour, Bashar;Shyr, Yu;Murphy, Patrick;Netterville, James L.;Yarbrough, Wendell G.;Cmelak, Anthony J.

    Abstract Background. Intensity-modulated radiation therapy (IMRT) and alternative chemotherapy regimens strive to maintain efficacy while minimizing toxicity in locally advanced head and neck cancer (LAHNC) treatment. Our experience with concurrent IMRT and taxane-based chemotherapy is presented.Methods. A retrospective review of 150 consecutive patients with LAHNC treated with IMRT and concurrent taxane-based chemotherapy with curative intent was performed. The IMRT fractionation regimen consisted of 69.3 Gy to gross disease (2.1 Gy/fraction) and 56.1 Gy to prophylactic nodal sites (1.7 Gy/fraction). Weekly paclitaxel (30 mg/m2) and carboplatin (area under the concentration–time curve [AUC], 1) were given concurrently to all patients, and 69% received weekly induction with paclitaxel (60 mg/m2) and carboplatin (AUC, 2).Results. Over 90% of patients received the prescribed radiation dose. Ninety-six percent completed five or more cycles of concurrent chemotherapy, with similar ...


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

Ressources et infrastructures (Traitements)

Cet article passe en revue les enjeux techniques, juridiques et éthiques associés à l'exploitation de bases de données rassemblant des dossiers médicaux électroniques

  • Mining electronic health records: towards better research applications and clinical care
    Nature Reviews Genetics, sous presse, 2012 (résumé)
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    Cet article passe en revue les enjeux techniques, juridiques et éthiques associés à l'exploitation de bases de données rassemblant des dossiers médicaux électroniques

    “Mining electronic health records: towards better research applications and clinical care”

    • Jensen, Peter B.;Jensen, Lars J.;Brunak, Soren

    Clinical data describing the phenotypes and treatment of patients represents an underused data source that has much greater research potential than is currently realized. Mining of electronic health records (EHRs) has the potential for establishing new patient-stratification principles and for revealing unknown disease correlations. Integrating EHR data with genetic data will also give a finer understanding of genotype–phenotype relationships. However, a broad range of ethical, legal and technical reasons currently hinder the systematic deposition of these data in EHRs and their mining. Here, we consider the potential for furthering medical research and clinical care using EHR data and the challenges that must be overcome before this is a reality.


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

Cet article évalue la faisabilité de mettre en application, au sein de la communauté des essais cliniques, les principes techniques et sociaux inventés par le mouvement des logiciels libres

  • Learning from Hackers: Open-Source Clinical Trials
    Science Translational Medicine, Vol. 4 (132), pp. 132cm5, 2012 (résumé)
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    Cet article évalue la faisabilité de mettre en application, au sein de la communauté des essais cliniques, les principes techniques et sociaux inventés par le mouvement des logiciels libres

    “Learning from Hackers: Open-Source Clinical Trials”

    • Dunn, Adam G.;Day, Richard O.;Mandl, Kenneth D.;Coiera, Enrico

    Open sharing of clinical trial data has been proposed as a way to address the gap between the production of clinical evidence and the decision-making of physicians. A similar gap was addressed in the software industry by their open-source software movement. Here, we examine how the social and technical principles of the movement can guide the growth of an open-source clinical trial community.


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

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