Traitements

Menée sur 36 patients atteints d'un mésothéliome pleural non résécable, cette étude évalue la faisabilité et la toxicité d'une approche thérapeutique utilisant la radiothérapie avec modulation d'intensité

• Pleural Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur 36 patients atteints d'un mésothéliome pleural non résécable, cette étude évalue la faisabilité et la toxicité d'une approche thérapeutique utilisant la radiothérapie avec modulation d'intensité

  “Pleural Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma”

  • Rosenzweig, Kenneth E.;Zauderer, Marjorie G.;Laser, Benjamin;Krug, Lee M.;Yorke, Ellen;Sima, Camelia S.;Rimner, Andreas;Flores, Raja;Rusch, Valerie

  In patients with malignant pleural mesothelioma who are unable to undergo pneumonectomy, it is difficult to deliver tumoricidal radiation doses to the pleura without significant toxicity. We have implemented a technique of using intensity-modulated radiotherapy (IMRT) to treat these patients, and we report the feasibility and toxicity of this approach. Between 2005 and 2010, 36 patients with malignant pleural mesothelioma and two intact lungs (i.e., no previous pneumonectomy) were treated with pleural IMRT to the hemithorax (median dose, 46.8 Gy; range, 41.4–50.4) at Memorial Sloan-Kettering Cancer Center. Of the 36 patients, 56% had right-sided tumors. The histologic type was epithelial in 78%, sarcomatoid in 6%, and mixed in 17%, and 6% had Stage I, 28% had Stage II, 33% had Stage III, and 33% had Stage IV. Thirty-two patients (89%) received induction chemotherapy (mostly cisplatin and pemetrexed); 56% underwent pleurectomy/decortication before IMRT and 44% did not undergo ...

  
  

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

Menée sur 116 patients atteints d'un carcinome sporadique isolé à cellules rénales traité entre 2003 et 2010 (durée médiane de suivi : 21 mois), cette étude rétrospective monocentrique évalue, du point de vue de la récidive locale et des complications associées au traitement, l'efficacité et la toxicité d'une cryoablation percutanée en fonction du stade de la tumeur au diagnostic

• Percutaneous cryoablation of solitary sporadic renal cell carcinomas
  • BJU International, sous presse, 2012 (résumé)
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  Menée sur 116 patients atteints d'un carcinome sporadique isolé à cellules rénales traité entre 2003 et 2010 (durée médiane de suivi : 21 mois), cette étude rétrospective monocentrique évalue, du point de vue de la récidive locale et des complications associées au traitement, l'efficacité et la toxicité d'une cryoablation percutanée en fonction du stade de la tumeur au diagnostic

  “Percutaneous cryoablation of solitary sporadic renal cell carcinomas”

  • Schmit, Grant D.;Thompson, R. Houston;Kurup, Anil N.;Weisbrod, Adam J.;Carter, Rickey E.;Callstrom, Matthew R.;Atwell, Thomas D.

  Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?Percutaneous renal cryoablation is a safe and effective treatment for patients with small renal masses, who are poor surgical candidates.Oncological outcomes from previous percutaneous ablation studies are difficult to interpret because of the large number of patients treated with a history of RCC (38% in our experience) and the large number of treated renal masses without a pathology-proven diagnosis. This cryoablation study addresses these issues by evaluating only solitary, sporadic biopsy-proven RCC. Oncological outcomes and complications were also evaluated by tumour T-stage, which allows some degree of comparison with previously published surgical results. OBJECTIVE * •To evaluate retrospectively our single institution experience with percutaneous cryoablation of solitary, sporadic renal cell carcinomas (RCCs), and to compare the efficacy and safety of this ...

  
  

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

Menée sur une cohorte européenne de 890 patients atteints d'un cancer de la prostate de stade pT3N0 et traités par prostatectomie radicale, cette étude comparative multicentrique montre qu'une radiothérapie de sauvetage précoce ne compromet pas le contrôle de la maladie et réduit le surtraitement associé à une radiothérapie adjuvante

• Early Salvage Radiation Therapy Does Not Compromise Cancer Control in Patients with pT3N0 Prostate Cancer After Radical Prostatectomy: Results of a Match-controlled Multi-institutional Analysis
  • European urology, sous presse, 2012 (résumé)
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  Menée sur une cohorte européenne de 890 patients atteints d'un cancer de la prostate de stade pT3N0 et traités par prostatectomie radicale, cette étude comparative multicentrique montre qu'une radiothérapie de sauvetage précoce ne compromet pas le contrôle de la maladie et réduit le surtraitement associé à une radiothérapie adjuvante

  “Early Salvage Radiation Therapy Does Not Compromise Cancer Control in Patients with pT3N0 Prostate Cancer After Radical Prostatectomy: Results of a Match-controlled Multi-institutional Analysis”

  • Alberto, Briganti;Thomas, Wiegel;Steven, Joniau;Cesare, Cozzarini;Marco, Bianchi;Maxine, Sun;Bertrand, Tombal;Karin, Haustermans;Tom, Budiharto;Wolfgang, Hinkelbein;Nadia Di, Muzio;Pierre, I. Karakiewicz;Francesco, Montorsi;Hein Van, Poppel

  Background : Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP). Objective : To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0R0–R1 PCa. Design, setting, and participants : Using a European multi-institutional cohort, 890 men with pT3pN0R0–R1 PCa were identified. Intervention : All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse. Outcome measurements and statistical analyses : Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as ...

  
  

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

Menée sur 67 patients atteints d'un lymphome orbital ou oculaire non hodgkinien et traités par radiothérapie externe, cette étude rétrospective évalue le risque de développer une rétinopathie postraitement en fonction de la dose de rayonnements ionisants délivrés, puis identifie les facteurs de risque et la nature des complications associées

• Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur 67 patients atteints d'un lymphome orbital ou oculaire non hodgkinien et traités par radiothérapie externe, cette étude rétrospective évalue le risque de développer une rétinopathie postraitement en fonction de la dose de rayonnements ionisants délivrés, puis identifie les facteurs de risque et la nature des complications associées

  “Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma”

  • Kaushik, Megha;Pulido, Jose S.;Schild, Steven E.;Stafford, Scott

  Radiation retinopathy is a potential long-term complication of radiation therapy to the orbit. The risk of developing this adverse effect is dose dependent; however, the threshold is unclear. The aim of this study was to identify the risk of developing radiation retinopathy at increasing radiation doses. A 40-year retrospective review was performed of patients who received external beam radiation therapy for ocular/orbital non-Hodgkin lymphoma (NHL). Sixty-seven patients who had at least one ophthalmic follow-up examination were included in this study. Most patients (52%) were diagnosed with NHL involving the orbit. Patients received external beam radiation therapy at doses between 1886 and 5400 cGy (mean, 3033 ± 782 cGy). Radiation retinopathy developed in 12% of patients, and the median time to diagnosis was 27 months (range, 15-241months). The mean prescribed radiation dose in patients with retinopathy was 3309 ± 585 cGy, and the estimated retinal dose (derived by reviewing the ...

  
  

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

Mené entre 2004 et 2007 sur 59 patientes atteintes d'un cancer du col de l'utérus (âge : 37 à 84 ans ; durée médiane de suivi : 24 mois), cet essai prospectif multicentrique japonais évalue l'incidence de fractures par insuffisance osseuse après une radiothérapie pelvienne, puis identifie les facteurs de risque associés

• Insufficiency Fractures After Pelvic Radiation Therapy for Uterine Cervical Cancer: An Analysis of Subjects in a Prospective Multi-institutional Trial, and Cooperative Study of the Japan Radiation Oncology Group (JAROG) and Japanese Radiation Oncology Stu
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Mené entre 2004 et 2007 sur 59 patientes atteintes d'un cancer du col de l'utérus (âge : 37 à 84 ans ; durée médiane de suivi : 24 mois), cet essai prospectif multicentrique japonais évalue l'incidence de fractures par insuffisance osseuse après une radiothérapie pelvienne, puis identifie les facteurs de risque associés

  “Insufficiency Fractures After Pelvic Radiation Therapy for Uterine Cervical Cancer: An Analysis of Subjects in a Prospective Multi-institutional Trial, and Cooperative Study of the Japan Radiation Oncology Group (JAROG) and Japanese Radiation Oncology Stu”

  • Tokumaru, Sunao;Toita, Takafumi;Oguchi, Masahiko;Ohno, Tatsuya;Kato, Shingo;Niibe, Yuzuru;Kazumoto, Tomoko;Kodaira, Takeshi;Kataoka, Masaaki;Shikama, Naoto;Kenjo, Masahiro;Yamauchi, Chikako;Suzuki, Osamu;Sakurai, Hideyuki;Teshima, Teruki;Kagami, Yoshikazu;Nakano, Takashi;Hiraoka, Masahiro;Mitsuhashi, Norio;Kudo, Sho

  To investigate pelvic insufficiency fractures (IF) after definitive pelvic radiation therapy for early-stage uterine cervical cancer, by analyzing subjects of a prospective, multi-institutional study. Between September 2004 and July 2007, 59 eligible patients were analyzed. The median age was 73 years (range, 37-84 years). The International Federation of Gynecologic Oncology and Obstetrics stages were Ib1 in 35, IIa in 12, and IIb in 12 patients. Patients were treated with the constant method, which consisted of whole-pelvic external-beam radiation therapy of 50 Gy/25 fractions and high-dose-rate intracavitary brachytherapy of 24 Gy/4 fractions without chemotherapy. After radiation therapy the patients were evaluated by both pelvic CT and pelvic MRI at 3, 6, 12, 18, and 24 months. Diagnosis of IF was made when the patients had both CT and MRI findings, neither recurrent tumor lesions nor traumatic histories. The CT findings of IF were defined as fracture lines or sclerotic linear ...

  
  

Mots clés : Col de l'utérus; Traitements (Traitements localisés : applications cliniques)

Menée sur 60 patients atteints d'un schwannome vestibulaire intracanaliculaire unilatéral sporadique, cette étude coréenne évalue la préservation de l'audition 1, 2 et 5 ans après une radiochirurgie stéréotaxique, et analyse la relation entre l'expansion transitoire du volume tumoral après le traitement et la perte des capacités auditives

• Hearing Outcomes After Stereotactic Radiosurgery for Unilateral Intracanalicular Vestibular Schwannomas: Implication of Transient Volume Expansion
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur 60 patients atteints d'un schwannome vestibulaire intracanaliculaire unilatéral sporadique, cette étude coréenne évalue la préservation de l'audition 1, 2 et 5 ans après une radiochirurgie stéréotaxique, et analyse la relation entre l'expansion transitoire du volume tumoral après le traitement et la perte des capacités auditives

  “Hearing Outcomes After Stereotactic Radiosurgery for Unilateral Intracanalicular Vestibular Schwannomas: Implication of Transient Volume Expansion”

  • Kim, Young-Hoon;Kim, Dong Gyu;Ho Han, Jung;Chung, Hyun-Tai;Kim, In Kyung;Song, Sang Woo;Park, Jeong-Hoon;Kim, Jin Wook;Kim, Yong Hwy;Park, Chul-Kee;Kim, Chae-Yong;Paek, Sun Ha;Jung, Hee-Won

  We evaluated the prognostic factors for hearing outcomes after stereotactic radiosurgery (SRS) for unilateral sporadic intracanalicular vestibular schwannomas (IC-VSs) as a clinical homogeneous group of VSs. Sixty consecutive patients with unilateral sporadic IC-VSs, defined as tumors in the internal acoustic canal, and serviceable hearing (Gardner-Roberson grade 1 or 2) were treated with SRS as an initial treatment. The mean tumor volume was 0.34 ± 0.03 cm3 (range, 0.03-1.00 cm3), and the mean marginal dose was 12.2 ± 0.1 Gy (range, 11.5-13.0 Gy). The median follow-up duration was 62 months (range, 36-141 months). The actuarial rates of serviceable hearing preservation were 70%, 63%, and 55% at 1, 2, and 5 years after SRS, respectively. In multivariate analysis, transient volume expansion of ≥20% from initial tumor size was a statistically significant risk factor for loss of serviceable hearing and hearing deterioration (increase of pure tone average ≥20 dB) (odds ratio = ...

  
  

Mots clés : Autres organes; Traitements (Traitements localisés : applications cliniques)

A partir de données administratives portant sur 1 124 patientes atteintes d'un cancer récidivant de l'ovaire, des trompes de Fallope ou du péritoine diagnostiqué entre 1990 et 2009, cette étude prospective monocentrique évalue l'intérêt d'une seconde cytoréduction chirurgicale pour améliorer la survie globale des patientes

• The Role of Secondary Cytoreductive Surgery in Patients with Recurrent Epithelial Ovarian, Tubal, and Peritoneal Cancers: A Comparative Effectiveness Analysis
  • The Oncologist, sous presse, 2012 (résumé)
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  A partir de données administratives portant sur 1 124 patientes atteintes d'un cancer récidivant de l'ovaire, des trompes de Fallope ou du péritoine diagnostiqué entre 1990 et 2009, cette étude prospective monocentrique évalue l'intérêt d'une seconde cytoréduction chirurgicale pour améliorer la survie globale des patientes

  “The Role of Secondary Cytoreductive Surgery in Patients with Recurrent Epithelial Ovarian, Tubal, and Peritoneal Cancers: A Comparative Effectiveness Analysis”

  • Chuang, Chi-Mu;Chou, Yiing-Jeng;Yen, Ming-Shyen;Chao, Kuan-Chong;Twu, Nae-Fang;Wu, Hua-Hsi;Wen, Kuo-Chang;Chen, Yi-Jen;Wang, Peng-Hui;Lai, Chung-Ru;Chou, Pesus

  Abstract Background. All published reports concerning secondary cytoreductive surgery for relapsed ovarian cancer have essentially been observational studies. However, the validity of observational studies is usually threatened from confounding by indication. We sought to address this issue by using comparative effectiveness methods to adjust for confounding.Methods. Using a prospectively collected administrative health care database in a single institution, we identified 1,124 patients diagnosed with recurrent epithelial, tubal, and peritoneal cancers between 1990 and 2009. Effectiveness of secondary cytoreductive surgery using the conventional Cox proportional hazard model, propensity score, and instrumental variable were compared. Sensitivity analyses for residual confounding were explored using an array approach.Results. Secondary cytoreductive surgery prolonged overall survival with a hazard ratio (95% confidence interval) of 0.76 (range 0.66–0.87), using the Cox proportional ...

  
  

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

Menée in vitro et sur un modèle murin, cette étude suggère d'utiliser un composé appelé PLX4720 pour traiter un astrocytome pédiatrique présentant la mutation BRAFV600E et des délétions du gène CDNK2A

• Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée in vitro et sur un modèle murin, cette étude suggère d'utiliser un composé appelé PLX4720 pour traiter un astrocytome pédiatrique présentant la mutation BRAFV600E et des délétions du gène CDNK2A

  “Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy”

  • Huillard, Emmanuelle;Hashizume, Rintaro;Phillips, Joanna J.;Griveau, Amélie;Ihrie, Rebecca A.;Aoki, Yasuyuki;Nicolaides, Theodore;Perry, Arie;Waldman, Todd;McMahon, Martin;Weiss, William A.;Petritsch, Claudia;James, C. David;Rowitch, David H.

  Although malignant astrocytomas are a leading cause of cancer-related death in children, rational therapeutic strategies are lacking. We previously identified activating mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (BRAFT1799A encoding BRAFV600E) in association with homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAFV600E expression in neural progenitors (NPs) is insufficient for tumorigenesis and increases NP cellular differentiation as well as apoptosis. In contrast, astrocytomas are readily generated from NPs with additional Ink4a-Arf deletion. The BRAFV600E inhibitor PLX4720 significantly increased survival of mice after intracranial transplant of genetically relevant murine or human astrocytoma cells. Moreover, combination therapy using PLX4720 plus the Cyclin-dependent kinase (CDK) 4/6-specific inhibitor PD0332991 further extended survival relative ...

  
  

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

Cet article passe en revue les perspectives offertes par les inhibiteurs d'ALK pour le traitement des neuroblastomes

• Targeting ALK in neuroblastoma-preclinical and clinical advancements
  • Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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  Cet article passe en revue les perspectives offertes par les inhibiteurs d'ALK pour le traitement des neuroblastomes

  “Targeting ALK in neuroblastoma-preclinical and clinical advancements”

  • Carpenter, Erica L.;Mosse, Yael P.

  Despite improvements in cancer therapies in the past 50 years, neuroblastoma remains a devastating clinical problem and a leading cause of childhood cancer deaths. Advances in treatments for children with high-risk neuroblastoma have, until recently, involved addition of cytotoxic therapy to dose-intensive regimens. In this era of targeted therapies, substantial efforts have been made to identify optimal targets for different types of cancer. The discovery of hereditary and somatic activating mutations in the oncogene ALK has now placed neuroblastoma among other cancers, such as melanoma and non-small-cell lung cancer (NSCLC), which benefit from therapies with oncogene-specific small-molecule tyrosine kinase inhibitors. Crizotinib, a small-molecule inhibitor of ALK, has transformed the landscape for the treatment of NSCLC harbouring ALK translocations and has demonstrated activity in preclinical models of ALK-driven neuroblastomas. However, inhibition of mutated ALK is complex when ...

  
  

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

Menée in vitro et sur des patients atteints d'un cancer métastatique du sein, cette étude évalue l’ajout d’un vaccin thérapeutique au daclizumab, un anticorps monoclonal anti CD25

• CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients
  • Science Translational Medicine, Vol. 4 (134), pp. 134ra62, 2012 (résumé)
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  Menée in vitro et sur des patients atteints d'un cancer métastatique du sein, cette étude évalue l’ajout d’un vaccin thérapeutique au daclizumab, un anticorps monoclonal anti CD25

  “CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients”

  • Rech, Andrew J.;Mick, Rosemarie;Martin, Sunil;Recio, Adri;Aqui, Nicole A.;Powell, Daniel J.;Colligon, Theresa A.;Trosko, Jennifer A.;Leinbach, Leah I.;Pletcher, Charles H.;Tweed, Carol K.;DeMichele, Angela;Fox, Kevin R.;Domchek, Susan M.;Riley, James L.;Vonderheide, Robert H.

  Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover, daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab ...

  
  

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

Menée sur 36 lignées cellulaires de cancer ovarien, cette étude identifie des voies de signalisation associées à la réponse au carboplatine, au cisplatine et au paclitaxel

• In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival
  • British Journal of Cancer, sous presse, 2012 (résumé)
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  Menée sur 36 lignées cellulaires de cancer ovarien, cette étude identifie des voies de signalisation associées à la réponse au carboplatine, au cisplatine et au paclitaxel

  “In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival”

  • Bicaku, E.;Xiong, Y.;Marchion, D. C.;Chon, H. S.;Stickles, X. B.;Chen, N.;Judson, P. L.;Hakam, A.;Gonzalez-Bosquet, J.;Wenham, R. M.;Apte, S. M.;Fulp, W.;Cubitt, C. L.;Chen, D. T.;Lancaster, J. M.

  Background: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. Methods: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin–paclitaxel (CPTX). For each cell line, IC50 levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC50 correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. Results: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), ...

  
  

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

Mené sur 184 patients atteints de diverses tumeurs solides, dont 156 atteints d'un mélanome métastatique, cet essai de phase I évalue le dabrafenib, un inhibiteur de l'activité kinase d'une version mutée du gène BRAF

• Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial
  • The Lancet, Vol. 379 (9829), pp. 1893-1901, 2012 (résumé)
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  Mené sur 184 patients atteints de diverses tumeurs solides, dont 156 atteints d'un mélanome métastatique, cet essai de phase I évalue le dabrafenib, un inhibiteur de l'activité kinase d'une version mutée du gène BRAF

  “Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial”

  • Falchook, Gerald S.;Long, Georgina V.;Kurzrock, Razelle;Kim, Kevin B.;Arkenau, Tobias H.;Brown, Michael P.;Hamid, Omid;Infante, Jeffrey R.;Millward, Michael;Pavlick, Anna C.;O?Day, Steven J.;Blackman, Samuel C.;Curtis, C. Martin;Lebowitz, Peter;Ma, Bo;Ouellet, Daniele;Kefford, Richard F.

  Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with ...

  
  
• Extending the reach of BRAF-targeted cancer therapy
  • The Lancet, Vol. 379 (9829), pp. 1858-1859, 2012 (commentaire)
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  Mené sur 184 patients atteints de diverses tumeurs solides, dont 156 atteints d'un mélanome métastatique, cet essai de phase I évalue le dabrafenib, un inhibiteur de l'activité kinase d'une version mutée du gène BRAF

  “Extending the reach of BRAF-targeted cancer therapy”

  • Gibney, Geoffrey T. ; Sondak, Vernon K.

  In The Lancet , Gerald Falchook and colleagues present results from a phase 1 trial of dabrafenib in patients with incurable solid tumours. In an expansion cohort, patients with BRAF-mutant tumours (including those with non-Val600Glu mutations) from three populations were treated at the recommended phase 2 dose: those with metastatic melanoma, those with non-melanoma solid tumours, and those with active melanoma brain metastases.

  
  

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

Menée sur un modèle murin de lymphome diffus à grandes cellules B, cette étude évalue l'activité antitumorale d'un composé appelé MLN0905, une petite molécule inhibitrice de PLK1, seul et en combinaison avec du rituximab

• MLN0905, A Small Molecule PLK1 Inhibitor, Induces Anti-Tumor Responses in Human Models of Diffuse Large B-cell Lymphoma
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée sur un modèle murin de lymphome diffus à grandes cellules B, cette étude évalue l'activité antitumorale d'un composé appelé MLN0905, une petite molécule inhibitrice de PLK1, seul et en combinaison avec du rituximab

  “MLN0905, A Small Molecule PLK1 Inhibitor, Induces Anti-Tumor Responses in Human Models of Diffuse Large B-cell Lymphoma”

  • Shi, Judy;Lasky, Kerri;Shinde, Vaishali;Stringer, Bradley;Qian, Mark G;Liao, Debra;Liu, Ray;Driscoll, Denise L;Nestor, Michelle T;Amidon, Benjamin S.;Rao, Youlan;Duffey, Matt O;Manfredi, Mark G.;Vos, Tricia J;D'Amore, Natalie R;Hyer, Marc L

  Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30 percent of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore experimental therapies continue to be investigated. We have discovered an experimental, potent and selective small molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and anti-tumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate MLN0905 modulates the pharmacodynamic biomarker phospho-Histone H3 (pHisH3) in tumor tissue. The anti-tumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant anti-tumor activity on both a ...

  
  

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

Menée in vitro, à l'aide de xénogreffes et sur des singes cynomolgus, cette étude évalue l'activité d'un anticorps monoclonal appelé CDX-1127 dans les leucémies et lymphomes CD27+

• Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Menée in vitro, à l'aide de xénogreffes et sur des singes cynomolgus, cette étude évalue l'activité d'un anticorps monoclonal appelé CDX-1127 dans les leucémies et lymphomes CD27+

  “Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia”

  • Vitale, Laura;He, Li-Zhen;Thomas, Lawrence J;Widger, Jennifer;Weidlick, Jeffrey;Crocker, Andrea;O'Neill, Thomas;Storey, James;Glennie, Martin J.;Grote, Deanna M.;Ansell, Stephen M.;Marsh, Henry;Keler, Tibor

  Purpose: The TNF receptor superfamily member, CD27 is best known for its important role in T cell immunity, but is also recognized as a cell-surface marker on a number of B and T cell malignancies. In this report, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27. Experimental Design: The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro. Severe combined immunodeficiency (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct anti-tumor effects. A pilot study of 1F5 was conducted in non-human primates to assess toxicity. Results: 1F5 binds with high affinity and specificity to human and macaque CD27, and competes with ligand binding. 1F5 activates T cells only in combination with T cell receptor stimulation, and does not induce proliferation of ...

  
  

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

Mené sur des lignées cellulaires et un modèle murin, cette étude évalue l'activité antitumorale et la toxicité du vandetanib, un composé dont le mécanisme d'action consiste à supprimer la phosphorylation des récepteurs VEGFR-2 et EGFR

• Vandetanib, an Inhibitor of VEGF Receptor-2 and EGF Receptor, Suppresses Tumor Development and Improves Prognosis of Liver Cancer in Mice
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Mené sur des lignées cellulaires et un modèle murin, cette étude évalue l'activité antitumorale et la toxicité du vandetanib, un composé dont le mécanisme d'action consiste à supprimer la phosphorylation des récepteurs VEGFR-2 et EGFR

  “Vandetanib, an Inhibitor of VEGF Receptor-2 and EGF Receptor, Suppresses Tumor Development and Improves Prognosis of Liver Cancer in Mice”

  • Inoue, Kinya;Torimura, Takuji;Nakamura, Toru;Iwamoto, Hideki;Masuda, Hiroshi;Abe, Mitsuhiko;Hashimoto, Osamu;Koga, Hironori;Ueno, Takato;Yano, Hirohisa;Sata, Michio

  Purpose: Vascular endothelial growth factor (VEGF), epithelial growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are expressed in hepatocellular carcinoma (HCC) and play a role in its growth. Vandetanib, a multi-kinase inhibitor, suppresses the phosphorylation of VEGF receptor 2 (VEGFR-2) and EGF receptor (EGFR). The aim of this study was to clarify the anti-tumor effect of vandetanib in mouse HCC. Experimental Design:We evaluated the effects of vandetanib on proliferation of human umbilical vein cells (HUVEC) and three hepatoma cell lines as well as the phosphorylation of VEGFR-2 and EGFR in these cells. Mice were implanted with hepatoma cells subcutaneously or orthotopically in the liver, and treated with 50 or 75 mg/kg vandetanib. We analyzed the effects of treatment on tumor cell proliferation and apoptosis, vessel density, phosphorylation of VEGFR-2 and EGFR, production of VEGF, TGF-alpha and EGF in tumor tissues. Adverse events on vandetanib administration ...

  
  

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

Menée à l'aide de xénogreffes, cette étude met en évidence un mécanisme impliquant les voies de signalisation de la bêta-caténine et FOXO3a dans l'apparition d'une résistance aux inhibiteurs de PI3K et AKT et dans le processus métastatique d'un cancer du côlon

• [beta]-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer
  • Nature Medicine, sous presse, 2012 (résumé)
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  Menée à l'aide de xénogreffes, cette étude met en évidence un mécanisme impliquant les voies de signalisation de la bêta-caténine et FOXO3a dans l'apparition d'une résistance aux inhibiteurs de PI3K et AKT et dans le processus métastatique d'un cancer du côlon

  “[beta]-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer”

  • Tenbaum, Stephan P.;Ordonez-Moran, Paloma;Puig, Isabel;Chicote, Irene;Arques, Oriol;Landolfi, Stefania;Fernandez, Yolanda;Herance, Jose Raul;Gispert, Juan D.;Mendizabal, Leire;Aguilar, Susana;Cajal, Santiago Ramon y;Schwartz, Simo;Vivancos, Ana;Espin, Eloy;Rojas, Santiago;Baselga, Jose;Tabernero, Josep;Munoz, Alberto;Palmer, Hector G.

  The Wnt– β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt – β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt – β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it ...

  
  

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

Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation PAK1 pour le traitement des cancers

• Molecular Pathways: Targeting P21-activated Kinase 1 Signaling in Cancer: Opportunities, Challenges and Limitations
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation PAK1 pour le traitement des cancers

  “Molecular Pathways: Targeting P21-activated Kinase 1 Signaling in Cancer: Opportunities, Challenges and Limitations”

  • Eswaran, Jeyanthy;Li, Da-Qiang;Shah, Anil;Kumar, Rakesh

  The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. The p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a plethora of its new functions in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely up-regulated in several human cancers including hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. The structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the ...

  
  

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

Cet article présente les résultats, après 8 ans de suivi, de l'essai PACS01 (Programme Action Concertée Sein 01) ayant évalué un traitement comprenant l'administration de docétaxel après une chimiothérapie FEC100 chez les patientes atteintes d'un cancer du sein opérable avec envahissement ganglionnaire

• Extended Benefit from Sequential Administration of Docetaxel after Standard Fluorouracil, Epirubicin, and Cyclophosphamide Regimen for Node-Positive Breast Cancer: The 8-Year Follow-Up Results of the UNICANCER-PACS01 Trial
  • The Oncologist, sous presse, 2012 (résumé)
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  Cet article présente les résultats, après 8 ans de suivi, de l'essai PACS01 (Programme Action Concertée Sein 01) ayant évalué un traitement comprenant l'administration de docétaxel après une chimiothérapie FEC100 chez les patientes atteintes d'un cancer du sein opérable avec envahissement ganglionnaire

  “Extended Benefit from Sequential Administration of Docetaxel after Standard Fluorouracil, Epirubicin, and Cyclophosphamide Regimen for Node-Positive Breast Cancer: The 8-Year Follow-Up Results of the UNICANCER-PACS01 Trial”

  • Coudert, Bruno;Asselain, Bernard;Campone, Mario;Spielmann, Marc;Machiels, Jean-Pascal;Pénault-Llorca, Frédérique;Serin, Daniel;Levy, Christelle;Romieu, Gilles;Canon, Jean-Luc;Orfeuvre, Hubert;Piot, Gilles;Petit, Thierry;Jerusalem, Guy;Audhuy, Bruno;Veyret, Corinne;Beauduin, Marc;Eymard, Jean-Christophe;Martin, Anne-Laure;Roché, Henri

  Abstract Purpose. The initial report from the Programme Action Concertée Sein (PACS) PACS01 trial demonstrated a benefit at 5 years for disease-free survival (DFS) and overall survival (OS) rates with the sequential administration of docetaxel after FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) for patients with node-positive, operable breast cancer. We evaluate here the impact of this regimen at 8 years.Patients and Methods. Between June 1997 and March 2000, a total of 1,999 patients (age <65) with localized, resectable, non-pretreated, unilateral breast cancer were randomly assigned to receive either standard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m2 docetaxel (FEC-D), both given every 21 days. Radiotherapy was mandatory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients. Five-year DFS was the trial’s main endpoint. Updated 8-year survival data are ...

  
  

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

Mené sur 369 patients atteints d'un sarcome avancé non adipocytaire des tissus mous, cet essai de phase III évalue, du point de vue de la survie sans progression, le pazopanib après l'échec d'une chimiothérapie standard

• Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial
  • The Lancet, sous presse, 2012 (résumé)
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  Mené sur 369 patients atteints d'un sarcome avancé non adipocytaire des tissus mous, cet essai de phase III évalue, du point de vue de la survie sans progression, le pazopanib après l'échec d'une chimiothérapie standard

  “Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial”

  • van der Graaf, Winette T. A.;Blay, Jean-Yves;Chawla, Sant P.;Kim, Dong-Wan;Bui-Nguyen, Binh;Casali, Paolo G.;Schöffski, Patrick;Aglietta, Massimo;Staddon, Arthur P.;Beppu, Yasuo;Le Cesne, Axel;Gelderblom, Hans;Judson, Ian R.;Araki, Nobuhito;Ouali, Monia;Marreaud, Sandrine;Hodge, Rachel;Dewji, Mohammed R.;Coens, Corneel;Demetri, George D.;Fletcher, Christopher D.;Dei Tos, Angelo Paolo;Hohenberger, Peter

  Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered ...

  
  
• Pazopanib and the treatment palette for soft-tissue sarcoma
  • The Lancet, sous presse, 2012 (commentaire)
  Détails

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  Mené sur 369 patients atteints d'un sarcome avancé non adipocytaire des tissus mous, cet essai de phase III évalue, du point de vue de la survie sans progression, le pazopanib après l'échec d'une chimiothérapie standard

  “Pazopanib and the treatment palette for soft-tissue sarcoma”

  • Bramwell, Vivien H. C.

  
  

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

Cet article passe en revue les avancées récentes concernant les différentes modalités d'une radiothérapie ou d'une chimioradiothérapie pour traiter un carcinome épidermoïde de la tête et du cou, associé au tabagisme ou au papillomavirus humain et de stade localement avancé, puis analyse le rôle des thérapies ciblées et personnalisées dans la prise en charge des patients

• Current issues in combined modality therapy in locally advanced head and neck cancer
  • Critical Reviews in Oncology/Hematology, sous presse, 2012 (résumé)
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  Cet article passe en revue les avancées récentes concernant les différentes modalités d'une radiothérapie ou d'une chimioradiothérapie pour traiter un carcinome épidermoïde de la tête et du cou, associé au tabagisme ou au papillomavirus humain et de stade localement avancé, puis analyse le rôle des thérapies ciblées et personnalisées dans la prise en charge des patients

  “Current issues in combined modality therapy in locally advanced head and neck cancer”

  • Cmelak, Anthony J.

  Curative treatment for patients with locally advanced squamous cell carcinomas of the head and neck (SCCHN) is complex and multidisciplinary. Our understanding of the optimal management of this disease has improved over the years, incorporating refined surgical approaches, better radiotherapy delivery methods, and greater use of systemic therapies. Investigation into shifting epidemiology patterns has uncovered two biologically and clinically distinct diseases: the smoking-related entity and the increasingly common malignancy associated with human papilloma virus (HPV). Prognosis favors the latter, driving newer investigations into dose de-intensification to limit toxicities in patients with HPV-driven disease, and alternatively intensifying treatment to improve tumor control in those with a significant smoking history. In this review, I describe the most recent progress in the multi-modal integration of radiotherapy and chemoradiotherapy, and the role of targeted agents and ...

  
  

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

Mené sur 75 patientes atteintes d'un cancer du sein de stade précoce et traitées de décembre 2003 à novembre 2005 (âge : 31 à 81 ans ; durée médiane de suivi : 69 mois), cet essai de phase II évalue, du point de vue du contrôle local à 5 ans, l'efficacité d'un traitement combinant une radiothérapie hypofractionnée avec modulation d'intensité et une dose de rayonnement additionnel du lit tumoral

• Five-year Local Control in a Phase II Study of Hypofractionated Intensity Modulated Radiation Therapy With an Incorporated Boost for Early Stage Breast Cancer
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Mené sur 75 patientes atteintes d'un cancer du sein de stade précoce et traitées de décembre 2003 à novembre 2005 (âge : 31 à 81 ans ; durée médiane de suivi : 69 mois), cet essai de phase II évalue, du point de vue du contrôle local à 5 ans, l'efficacité d'un traitement combinant une radiothérapie hypofractionnée avec modulation d'intensité et une dose de rayonnement additionnel du lit tumoral

  “Five-year Local Control in a Phase II Study of Hypofractionated Intensity Modulated Radiation Therapy With an Incorporated Boost for Early Stage Breast Cancer”

  • Freedman, Gary M.;Anderson, Penny R.;Bleicher, Richard J.;Litwin, Samuel;Li, Tianyu;Swaby, Ramona F.;Ma, Chang-Ming Charlie;Li, Jinsheng;Sigurdson, Elin R.;Watkins-Bruner, Deborah;Morrow, Monica;Goldstein, Lori J.

  Conventional radiation fractionation of 1.8-2 Gy per day for early stage breast cancer requires daily treatment for 6-7 weeks. We report the 5-year results of a phase II study of intensity modulated radiation therapy (IMRT), hypofractionation, and incorporated boost that shortened treatment time to 4 weeks. The study design was phase II with a planned accrual of 75 patients. Eligibility included patients aged ≥18 years, Tis-T2, stage 0-II, and breast conservation. Photon IMRT and an incorporated boost was used, and the whole breast received 2.25 Gy per fraction for a total of 45 Gy, and the tumor bed received 2.8 Gy per fraction for a total of 56 Gy in 20 treatments over 4 weeks. Patients were followed every 6 months for 5 years. Seventy-five patients were treated from December 2003 to November 2005. The median follow-up was 69 months. Median age was 52 years (range, 31-81). Median tumor size was 1.4 cm (range, 0.1-3.5). Eighty percent of tumors were node negative; 93% of patients ...

  
  

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

Mené au Japon entre 2003 et 2010 sur 200 patients atteints d'un cancer du poumon non à petites cellules de stade III et non résécable (âge : supérieur à 70 ans), cet essai randomisé de phase III évalue l'intérêt de combiner une faible dose quotidienne de carboplatine avec une radiothérapie thoracique pour améliorer la survie globale des patients

• Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301)
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené au Japon entre 2003 et 2010 sur 200 patients atteints d'un cancer du poumon non à petites cellules de stade III et non résécable (âge : supérieur à 70 ans), cet essai randomisé de phase III évalue l'intérêt de combiner une faible dose quotidienne de carboplatine avec une radiothérapie thoracique pour améliorer la survie globale des patients

  “Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301)”

  • Atagi, Shinji;Kawahara, Masaaki;Yokoyama, Akira;Okamoto, Hiroaki;Yamamoto, Nobuyuki;Ohe, Yuichiro;Sawa, Toshiyuki;Ishikura, Satoshi;Shibata, Taro;Fukuda, Haruhiko;Saijo, Nagahiro;Tamura, Tomohide

  It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC. This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m2per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0vs1vs2), stage (IIIAvsIIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a ...

  
  
• Treating elderly patients with stage III NSCLC
  • The Lancet Oncology, sous presse, 2012 (commentaire)
  Détails

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  Mené au Japon entre 2003 et 2010 sur 200 patients atteints d'un cancer du poumon non à petites cellules de stade III et non résécable (âge : supérieur à 70 ans), cet essai randomisé de phase III évalue l'intérêt de combiner une faible dose quotidienne de carboplatine avec une radiothérapie thoracique pour améliorer la survie globale des patients

  “Treating elderly patients with stage III NSCLC”

  • Wisnivesky, Juan P. ; Strauss, Gary M.

  
  

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

A partir de deux essais de phase I incluant au total 32 patients atteints d'une leucémie myéloïde aiguë de stade avancé ou d'une leucémie lymphoblastique aiguë et bénéficiant d'une greffe allogénique de cellules hématopoïétiques (âges médians : 33 ans et 41 ans), cette étude évalue l'efficacité et la toxicité de deux protocoles d'irradiation totale de la moelle osseuse par escalade de doses en combinaison avec une chimiothérapie concomitante

• Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
  Détails

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  A partir de deux essais de phase I incluant au total 32 patients atteints d'une leucémie myéloïde aiguë de stade avancé ou d'une leucémie lymphoblastique aiguë et bénéficiant d'une greffe allogénique de cellules hématopoïétiques (âges médians : 33 ans et 41 ans), cette étude évalue l'efficacité et la toxicité de deux protocoles d'irradiation totale de la moelle osseuse par escalade de doses en combinaison avec une chimiothérapie concomitante

  “Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation”

  • Wong, Jeffrey Y. C.;Forman, Stephen;Somlo, George;Rosenthal, Joseph;Liu, An;Schultheiss, Timothy;Radany, Eric;Palmer, Joycelynne;Stein, Anthony

  We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Trial 1 consisted of TMI on Days −10 to −6, etoposide (VP16) on Day −5 (60 mg/kg), and cyclophosphamide (CY) on Day −3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days −12 to −8 (800 μM min), TMI on Days −8 to −4, and VP16 on Day −3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Trial 1 had 12 patients with ...

  
  

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

Mené sur 248 patients atteints d'un cancer rectal localement avancé, cet essai randomisé de phase III compare, du point de vue de la rémission complète, l'efficacité et la toxicité de 2 doses de rayonnements ionisants pré-opératoires en combinaison avec une chimiothérapie concomitante

• Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
  Détails

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  Mené sur 248 patients atteints d'un cancer rectal localement avancé, cet essai randomisé de phase III compare, du point de vue de la rémission complète, l'efficacité et la toxicité de 2 doses de rayonnements ionisants pré-opératoires en combinaison avec une chimiothérapie concomitante

  “Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses”

  • Jakobsen, Anders;Ploen, John;Vuong, Té;Appelt, Ane;Lindebjerg, Jan;Rafaelsen, Soren R.

  Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation. The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of ≤5 mm on magnetic resonance imaging. The patients were randomized to receive 50.4 Gy in 28 fractions to the tumor and pelvic lymph nodes (arm A) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy (10 Gy in 2 fractions; arm B). Concomitant chemotherapy, uftoral 300 mg/m2 and L-leucovorin 22.5 mg/d, was added to both arms on treatment days. The primary endpoint was complete pathologic remission. The secondary endpoints included tumor response and rate of complete resection (R0). The study included 248 patients. No significant difference was found in toxicity or surgical ...

  
  

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

Cet article passe en revue les différents modèles murins utilisés pour l'étude des mécanismes de résistance aux traitements anticancéreux

• Using mice to unveil the genetics of cancer resistance
  • Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, sous presse, 2012 (résumé)
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  Cet article passe en revue les différents modèles murins utilisés pour l'étude des mécanismes de résistance aux traitements anticancéreux

  “Using mice to unveil the genetics of cancer resistance”

  • van der Weyden, Louise;Adams, David J.

  In the UK, four in ten people will develop some form of cancer during their lifetime, with an individual's relative risk depending on many factors, including age, lifestyle and genetic make-up. Much research has gone into identifying the genes that are mutated in tumorigenesis with the over-whelming majority of genetically-modified (GM) mice in cancer research showing accelerated tumorigenesis or recapitulating key aspects of the tumorigenic process. Yet if six out of ten people will not develop some form of cancer during their lifetime, together with the fact that some cancer patients experience spontaneous regression/remission, it suggests there are ways of ‘resisting’ cancer. Indeed, there are wildtype, spontaneously-arising mutants and GM mice that show some form of ‘resistance’ to cancer. Identification of mice with increased resistance to cancer is a novel aspect of cancer research that is important in terms of providing both chemopreventative and therapeutic options. In ...

  
  

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

A partir de données portant sur la période 2001-2010, cette étude compare les délais d'autorisation de mise sur le marché de nouveaux médicaments au sein des agences de réglementation américaine, européenne et canadienne

• Regulatory Review of Novel Therapeutics — Comparison of Three Regulatory Agencies
  • New England Journal of Medicine, sous presse, 2012 (article en libre accès)
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  A partir de données portant sur la période 2001-2010, cette étude compare les délais d'autorisation de mise sur le marché de nouveaux médicaments au sein des agences de réglementation américaine, européenne et canadienne

  “Regulatory Review of Novel Therapeutics — Comparison of Three Regulatory Agencies”

  • Downing, Nicholas S.;Aminawung, Jenerius A.;Shah, Nilay D.;Braunstein, Joel B.;Krumholz, Harlan M.;Ross, Joseph S.

  Background: The upcoming reauthorization of the Prescription Drug User Fee Act focuses on improving the review process for new drug applications at the Food and Drug Administration (FDA). Methods: Using publicly available information from the FDA, the European Medicines Agency (EMA), and Health Canada, we compared the time for completion of the first review and the total review time for all applications involving novel therapeutic agents approved by the three regulatory agencies from 2001 through 2010 and determined the geographic area in which each novel therapeutic agent was first approved for use. Results: There were 510 applications for novel therapeutic agents approved from 2001 through 2010 — 225 by the FDA, 186 by the EMA, and 99 by Health Canada; among the applications, there were 289 unique agents. The median length of time for completion of the first review was 303 days (interquartile range, 185 to 372) for applications approved by the FDA, 366 days (interquartile range, ...

  
  

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

A partir d'une revue systématique de la littérature en matière d'essais cliniques randomisés publiés entre 2005 et 2007 dans les cinq principaux journaux médicaux (235 articles), cette étude évalue l'impact du nombre de patients perdus de vue sur l'interprétation des résultats

• Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review
  • British Medical Journal, Vol. 344, 2012 (article en libre accès)
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  A partir d'une revue systématique de la littérature en matière d'essais cliniques randomisés publiés entre 2005 et 2007 dans les cinq principaux journaux médicaux (235 articles), cette étude évalue l'impact du nombre de patients perdus de vue sur l'interprétation des résultats

  “Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review”

  • Elie A Akl;Matthias Briel;John J You;Xin Sun;Bradley C Johnston;Jason W Busse;Sohail Mulla;Francois Lamontagne;Dirk Bassler;Claudio Vera;Mohamad Alshurafa;Christina M Katsios;Qi Zhou;Tali Cukierman-Yaffe;Azim Gangji;Edward J Mills;Stephen D Walter;Deborah J Cook;Holger J Schünemann;Douglas G Altman;Gordon H Guyatt

  Objective: To assess the reporting, extent, and handling of loss to follow-up and its potential impact on the estimates of the effect of treatment in randomised controlled trials. Design: Systematic review. We calculated the percentage of trials for which the relative risk would no longer be significant under a number of assumptions about the outcomes of participants lost to follow-up. Data sources : Medline search of five top general medical journals, 2005-07. Eligibility criteria : Randomised controlled trials that reported a significant binary primary patient important outcome. Results : Of the 235 eligible reports identified, 31 (13%) did not report whether or not loss to follow-up occurred. In reports that did give the relevant information, the median percentage of participants lost to follow-up was 6% (interquartile range 2-14%). The method by which loss to follow-up was handled was unclear in 37 studies (19%); the most commonly used method was survival analysis (66, 35%). ...

  
  

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