Traitements

Menée sur 3 cohortes incluant au total 2 036 femmes atteintes d'un cancer du sein, cette étude évalue l'association entre des polymorphismes situés près du gène du TNFalpha et le risque d'événements indésirables liés aux rayonnements ionisants

• A replicated association between polymorphisms near TNF[alpha] and risk for adverse reactions to radiotherapy
  • British Journal of Cancer, sous presse, 2012 (résumé)
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  Menée sur 3 cohortes incluant au total 2 036 femmes atteintes d'un cancer du sein, cette étude évalue l'association entre des polymorphismes situés près du gène du TNFalpha et le risque d'événements indésirables liés aux rayonnements ionisants

  “A replicated association between polymorphisms near TNF[alpha] and risk for adverse reactions to radiotherapy”

  • Talbot, C. J.;Tanteles, G. A.;Barnett, G. C.;Burnet, N. G.;Chang-Claude, J.;Coles, C. E.;Davidson, S.;Dunning, A. M.;Mills, J.;Murray, R. J. S.;Popanda, O.;Seibold, P.;West, C. M. L.;Yarnold, J. R.;Symonds, R. P.

  Background : Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. Methods : We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. Results : Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52–3.98). Conclusion : We have ...

  
  

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

Menée sur 241 patients atteints d'un cancer localisé de la prostate et ayant reçu pour la plupart d'entre eux un traitement anti-androgénique néoadjuvant ou adjuvant, cette étude rétrospective évalue la toxicité aiguë et la toxicité tardive d'une radiothérapie avec modulation d'intensité basée sur la tomothérapie hélicoïdale (durée médiane de suivi après le début du traitement : 35 mois)

• Preliminary results of intensity-modulated radiation therapy with helical tomotherapy for prostate cancer
  • Journal of Cancer Research and Clinical Oncology, sous presse, 2012 (résumé)
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  Menée sur 241 patients atteints d'un cancer localisé de la prostate et ayant reçu pour la plupart d'entre eux un traitement anti-androgénique néoadjuvant ou adjuvant, cette étude rétrospective évalue la toxicité aiguë et la toxicité tardive d'une radiothérapie avec modulation d'intensité basée sur la tomothérapie hélicoïdale (durée médiane de suivi après le début du traitement : 35 mois)

  “Preliminary results of intensity-modulated radiation therapy with helical tomotherapy for prostate cancer”

  • Tomita, Natsuo;Soga, Norihito;Ogura, Yuji;Hayashi, Norio;Shimizu, Hidetoshi;Kubota, Takashi;Ito, Junji;Hirata, Kimiko;Ohshima, Yukihiko;Tachibana, Hiroyuki;Kodaira, Takeshi

  Purpose We present the preliminary results of intensity-modulated radiation therapy with helical tomotherapy (HT) for clinically localized prostate cancer. Methods Regularly followed 241 consecutive patients, who were treated with HT between June 2006 and December 2010, were included in this retrospective study. Most patients received both relatively long-term neoadjuvant and adjuvant androgen deprivation therapy (ADT). Patients received 78 Gy in the intermediate high-risk group and 74 Gy in the low-risk group. Biochemical disease-free survival (bDFS) followed the Phoenix definition. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. Results The median follow-up time from the start date of HT was 35 months. The rates of acute Grade 2 gastro-intestinal (GI) and genitor-urinary (GU) toxicities were 11.2 and 24.5 %. No patients experienced acute Grade 3 or higher symptoms. The rates of late Grade 2 and 3 GI toxicities were 6.6 and 0.8 %, and ...

  
  

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

A partir de données administratives portant sur 370 patients atteints d'un cancer de la prostate à risque élevé de récidive, cette étude prospective évalue, du point de vue de la survie sans récivive biochimique, de la survie sans progression et de la mortalité spécifique, les résultats à 10 ans d'une prostatectomie radicale par laparoscopie en fonction du stade de la maladie au diagnostic

• Long-term oncological outcomes after laparoscopic radical prostatectomy
  • BJU International, sous presse, 2012 (résumé)
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  A partir de données administratives portant sur 370 patients atteints d'un cancer de la prostate à risque élevé de récidive, cette étude prospective évalue, du point de vue de la survie sans récivive biochimique, de la survie sans progression et de la mortalité spécifique, les résultats à 10 ans d'une prostatectomie radicale par laparoscopie en fonction du stade de la maladie au diagnostic

  “Long-term oncological outcomes after laparoscopic radical prostatectomy”

  • Hruza, Marcel;Bermejo, Justo Lorenzo;Flinspach, Bettina;Schulze, Michael;Teber, Dogu;Joachim Rumpelt, Hans;Jochen Rassweiler, Jens

  Study Type – Therapy (outcomes)Level of Evidence 2b“What's known on the subject?” and “What does the study add?”Laparoscopic radical prostatectomy (LRP) has shown good oncological short-term and mid-term outcomes, but long-term outcomes are still lacking.We present long-term oncological outcomes of LRP in a large cohort of patients operated on in one of the pioneering European centres. The data from the present study show high rates of biochemical and clinical recurrence-free survival and low cancer-specific mortality compared with open series. OBJECTIVES * •To investigate long-term oncological outcomes after laparoscopic radical prostatectomy (LRP). * •To identify parameters influencing recurrence-free survival in a single-institution series. PATIENTS AND METHODS * •All patients underwent LRP using the transperitoneal retrograde Heilbronn technique. High-risk patients received adjuvant treatment according to an institutional algorithm based on prostate-specific ...

  
  

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

A partir des données d'un registre américain du cancer portant sur une cohorte de 18 015 patients atteints d'un cancer de la prostate diagnostiqué entre 2001 et 2007, cette étude compare, du point de vue de l'utilisation d'une thérapie de sauvetage et des événements indésirables, l'efficacité d'une radiothérapie avec modulation d'intensité et d'une radiothérapie conformationnelle 3D

• Comparative Effectiveness of External-Beam Radiation Approaches for Prostate Cancer
  • European urology, sous presse, 2012 (résumé)
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  A partir des données d'un registre américain du cancer portant sur une cohorte de 18 015 patients atteints d'un cancer de la prostate diagnostiqué entre 2001 et 2007, cette étude compare, du point de vue de l'utilisation d'une thérapie de sauvetage et des événements indésirables, l'efficacité d'une radiothérapie avec modulation d'intensité et d'une radiothérapie conformationnelle 3D

  “Comparative Effectiveness of External-Beam Radiation Approaches for Prostate Cancer”

  • Bruce, L. Jacobs;Yun, Zhang;Ted, A. Skolarus;John, T. Wei;James, E. Montie;David, C. Miller;Brent, K. Hollenbeck

  Background : Intensity-modulated radiotherapy (IMRT) is increasingly used to treat localized prostate cancer. Although allowing for the delivery of higher doses of radiation to the prostate, its effectiveness compared with the prior standard three-dimensional conformal therapy (3D-CRT) is uncertain. Objective : To examine the comparative effectiveness of IMRT relative to 3D-CRT. Design, setting, and participants : We performed a population-based cohort study using Surveillance, Epidemiology, and End Results-Medicare data to identify men diagnosed with prostate cancer between 2001 and 2007 who underwent either 3D-CRT (n = 6976) or IMRT (n = 11 039). Outcome measurements and statistical analysis : We assessed our main outcomes (ie, the adjusted use of salvage therapy with androgen-deprivation therapy [ADT] and risk of a complication requiring an intervention) using Cox proportional hazards models. Results and limitations : The percentage of men receiving IMRT increased from 9% in 2001 ...

  
  

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

Menée sur 116 patientes atteintes d'un cancer localement avancé du col de l'utérus et traitées entre 1996 et 2009, cette étude évalue, du point de vue du contrôle de la maladie et de la survie, l'efficacité et la toxicité d'une brachythérapie interstitielle à forte dose de rayonnements en combinaison avec une radiothérapie externe

• Outcomes of High-Dose-Rate Interstitial Brachytherapy in the Treatment of Locally Advanced Cervical Cancer: Long-term Results
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur 116 patientes atteintes d'un cancer localement avancé du col de l'utérus et traitées entre 1996 et 2009, cette étude évalue, du point de vue du contrôle de la maladie et de la survie, l'efficacité et la toxicité d'une brachythérapie interstitielle à forte dose de rayonnements en combinaison avec une radiothérapie externe

  “Outcomes of High-Dose-Rate Interstitial Brachytherapy in the Treatment of Locally Advanced Cervical Cancer: Long-term Results”

  • Pinn-Bingham, Melva;Puthawala, Ajmel A.;Syed, A. M. Nisar;Sharma, Anil;DiSaia, Philip;Berman, Michael;Tewari, Krishnansu S.;Randall-Whitis, Leslie;Mahmood, Usama;Ramsinghani, Nilam;Kuo, Jeffrey;Chen, Wen-Pin;McLaren, Christine E.

  The purpose of this study was to determine locoregional control (LRC), disease-free survival (DFS), and toxicity of high-dose-rate interstitial brachytherapy (HDR-ISBT) in the treatment of locally advanced cervical cancer. Between March 1996 and May 2009, 116 patients with cervical cancer were treated. Of these, 106 (91%) patients had advanced disease (International Federation of Gynecology and Obstetrics stage IIB-IVA). Ten patients had stage IB, 48 had stage II, 51 had stage III, and 7 had stage IVA disease. All patients were treated with a combination of external beam radiation therapy (EBRT) to the pelvis (5040 cGy) and 2 applications of HDR-ISBT to a dose of 3600 cGy to the implanted volume. Sixty-one percent of patients also received interstitial hyperthermia, and 94 (81%) patients received chemotherapy. Clinical LRC was achieved in 99 (85.3%) patients. Three-year DFS rates were 59%, 67%, 71%, and 57% for patients with stage IB, II, III, and IVA disease, respectively. The 5-year ...

  
  

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

A partir d'une revue systématique de la littérature (19 études observationnelles, 9 études rétrospectives, 1 méta-analyse, 1 essai), cette étude compare, du point de vue des événements indésirables et de la survie spécifique, l'efficacité de différentes techniques chirurgicales pour traiter un carcinome à cellules transitionnelles des voies urinaires supérieures

• Surgical management for upper urinary tract transitional cell carcinoma (UUT-TCC): a systematic review
  • BJU International, sous presse, 2012 (résumé)
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  A partir d'une revue systématique de la littérature (19 études observationnelles, 9 études rétrospectives, 1 méta-analyse, 1 essai), cette étude compare, du point de vue des événements indésirables et de la survie spécifique, l'efficacité de différentes techniques chirurgicales pour traiter un carcinome à cellules transitionnelles des voies urinaires supérieures

  “Surgical management for upper urinary tract transitional cell carcinoma (UUT-TCC): a systematic review”

  • Rai, Bhavan Prasad;Shelley, Mike;Coles, Bernadette;Somani, Bhaskar;Nabi, Ghulam

  What's known on the subject? and What does the study add? Upper urinary tract transitional cell carcinoma (UUT-TCC) is an aggressive disease. The mainstay in the treatment of UUT-TCC is surgical intervention, with oncological control the primary objective. UUT-TCCs have been conventionally treated with radical nephroureterectomy (NU). This procedure involves removal of the kidney, ureter and ipsilateral excision of a bladder cuff. Whilst open NU has traditionally been the approach used, laparoscopic NU (LNU) is now an increasingly popular and established approach for UUT-TCC. It is argued that LNU reduces postoperative morbidity without compromising oncological efficacy. With technological evolution, robotic NU has now been attempted in some centres as well. In addition, several techniques have been described to manage the bladder cuff with no agreement as to the most efficacious approach. In a further attempt to reduce morbidity and safeguard nephrons, there have been advocates of a ...

  
  

Mots clés : Appareil urinaire (autre); Traitements (Traitements localisés : applications cliniques)

Menée sur 120 patients atteints d'une tumeur solide, cette étude évalue l'intérêt d'un système d'imagerie à balayage laser pour localiser les tumeurs et détecter les erreurs de configuration d'une radiothérapie fractionnée

• Clinical Evaluation of a Laser Surface Scanning System in 120 Patients for Improving Daily Setup Accuracy in Fractionated Radiation Therapy
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur 120 patients atteints d'une tumeur solide, cette étude évalue l'intérêt d'un système d'imagerie à balayage laser pour localiser les tumeurs et détecter les erreurs de configuration d'une radiothérapie fractionnée

  “Clinical Evaluation of a Laser Surface Scanning System in 120 Patients for Improving Daily Setup Accuracy in Fractionated Radiation Therapy”

  • Moser, Torsten;Habl, Gregor;Uhl, Matthias;Schubert, Kai;Sroka-Perez, Gabriele;Debus, Jürgen;Herfarth, Klaus;Karger, Christian P.

  To evaluate the clinical suitability of a specific optical surface imaging system to detect setup errors in fractionated radiation therapy. The setup correction accuracy of a 3-dimensional laser imaging system was analyzed for 6 different tumor locations with 20 patients each. For each patient, the setup corrections of the megavoltage computed tomography (MVCT) images of a TomoTherapy unit (TomoTherapy, Madison, WI) were compared with those of the laser system for the first 10 fractions. For the laser system, the reference surface either was obtained from the DICOM (Digital Imaging and Communications in Medicine) surface structure delineated on the planning computed tomography images or was acquired with the system itself at the first fraction after the MVCT-based setup correction. Data analysis was performed for both reference types. By use of the DICOM reference image, systematic shifts between 3 and 9 mm were found, depending on the tumor location. For the optical reference, no ...

  
  

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

Menée en Chine sur 147 patientes présentant des métastases ovariennes ayant pour origine un cancer primitif extra-génital (durée médiane de suivi : 48 mois), cette étude rétrospective analyse les caractéristiques pathologiques et cliniques de ces métastases, évalue l'intérêt d'une métastasectomie du point de vue de la survie globale et identifie les facteurs prédictifs associés

• Ovarian metastases resection from extragenital primary sites:outcome and prognostic factor analysis of 147 patients
  • BMC Cancer, Vol. 12 (1), pp. 278, 2012 (article en libre accès)
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  Menée en Chine sur 147 patientes présentant des métastases ovariennes ayant pour origine un cancer primitif extra-génital (durée médiane de suivi : 48 mois), cette étude rétrospective analyse les caractéristiques pathologiques et cliniques de ces métastases, évalue l'intérêt d'une métastasectomie du point de vue de la survie globale et identifie les facteurs prédictifs associés

  “Ovarian metastases resection from extragenital primary sites:outcome and prognostic factor analysis of 147 patients”

  • Li, Wen-Hua;Wang, Hua-Ying;Wang, Jian;LV, Fang-Fang;Zhu, Xiao-Dong;Wang, Zhong-Hua

  BACKGROUND:To explore the outcomes and prognostic factors of ovarian metastasectomy intervention on overall survival from extragenital primary cancer.METHODS:Patients with ovarian metastases from extragenital primary cancer confirmed by laparotomy surgery and ovarian metastases resection were retrospectively collected in a single institution during an 8-year period. A total of 147 cases were identified and primary tumor sites were colorectal region (49.0%), gastric (40.8%), breast (8.2%), biliary duct (1.4%) and liver (0.7%). The pathological and clinical features were evaluated. Patients' outcome with different primary tumor sites and predictive factors for overall survival were also investigated by univariate and multivariate analysis.RESULTS:Metachronous ovarian metastasis occurred in 92 (62.6%) and synchronous in 55 (37.4%) patients. Combined metastases occurred in 40 (27.2%). Bilateral metastasis was found in 97 (66%) patients. The median ovarian metastasis tumor size was 9 cm. ...

  
  

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

Menée sur des lignées cellulaires et 3 patients néerlandais atteints d'un carcinome du rhino-pharynx réfractaire aux traitements conventionnels, cette étude évalue les effets d'une stratégie thérapeutique à base de gemcitabine, d'acide valproïque et de valganciclovir pour le traitement de cancers liés au virus d'Epstein-Barr

• Cytolytic Virus Activation Therapy for Epstein-Barr Virus Driven Tumours
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Menée sur des lignées cellulaires et 3 patients néerlandais atteints d'un carcinome du rhino-pharynx réfractaire aux traitements conventionnels, cette étude évalue les effets d'une stratégie thérapeutique à base de gemcitabine, d'acide valproïque et de valganciclovir pour le traitement de cancers liés au virus d'Epstein-Barr

  “Cytolytic Virus Activation Therapy for Epstein-Barr Virus Driven Tumours”

  • Wildeman, Maarten A;Novalic, Zlata;Verkuijlen, Sandra AWM;Juwana, Hedy;Huitema, Alwin D.R.;Tan, Ing B.;Middeldorp, Jaap M;De Boer, Jan Paul;Greijer, Astrid E

  Purpose: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV). Since all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells EBV hides in a latent state and expresses only few non-immunogenic proteins for EBV maintenance and contributing to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition and inducing susceptibility to antiviral therapy. Experimental Design: CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as antiviral drug to block virus replication and kill proliferating virus infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC refractory to conventional treatment. Results: In NPC cell lines both GCb and VPA can induce the lytic cycle of EBV. Their combination ...

  
  

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

Menée sur des lignées cellulaires de cancer du sein résistantes au trastuzumab et au lapatinib, cette étude évalue l'activité antitumorale du dacomitinib, notamment dans les lignées HER2+

• Dacomitinib (PF-00299804), a irreversible pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée sur des lignées cellulaires de cancer du sein résistantes au trastuzumab et au lapatinib, cette étude évalue l'activité antitumorale du dacomitinib, notamment dans les lignées HER2+

  “Dacomitinib (PF-00299804), a irreversible pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib”

  • Kalous, Ondrej;Conklin, Dylan;Desai, Amrita J;O'Brien, Neil A;Ginther, Charles;Anderson, Lee;Cohen, David J;Britten, Carolyn D;Taylor, Ian;Christensen, James G.;Slamon, Dennis J.;Finn, Richard S.

  The human epidermal growth factor (HER) family of receptors have been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR = 3.39, p < 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with ...

  
  

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

Menée in vitro et in vivo, cette étude suggère qu'une protéase spécifique de l'ubiquitine, UBP43, est une cible thérapeutique potentielle dans le cancer du poumon

• Evidence for the Ubiquitin Protease UBP43 as an Antineoplastic Target
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude suggère qu'une protéase spécifique de l'ubiquitine, UBP43, est une cible thérapeutique potentielle dans le cancer du poumon

  “Evidence for the Ubiquitin Protease UBP43 as an Antineoplastic Target”

  • Guo, Yongli;Chinyengetere, Fadzai;Dolinko, Andrey V;Lopez-Aguiar, Alexandra;Lu, Yun;Galimberti, Fabrizio;Ma, Tian;Feng, Qing;Sekula, David;Freemantle, Sarah J.;Andrew, Angeline S;Memoli, Vincent A;Dmitrovsky, Ethan

  New pharmacologic targets are needed for lung cancer. One candidate pathway to target is composed of the E1-like ubiquitin-activating enzyme (UBE1L) that associates with interferon-stimulated gene 15 (ISG15), which complexes with and destabilizes cyclin D1. Ubiquitin protease 43 (UBP43/USP18) removes ISG15 from conjugated proteins. This study reports that gain of UBP43 stabilized cyclin D1, but not other D-type cyclins or cyclin E. This depended on UBP43 enzymatic activity; an enzymatically inactive UBP43 did not affect cyclin D1 stability. As expected, small interfering RNAs (siRNAs) that reduced UBP43 expression also decreased cyclin D1 levels and increased apoptosis in a panel of lung cancer cell lines. Forced cyclin D1 expression rescued UBP43 apoptotic effects, which highlighted the importance of cyclin D1 in conferring this. Short hairpin RNA (shRNA)-mediated reduction of UBP43 significantly increased apoptosis and reduced murine lung cancer growth in vitro and in vivo after ...

  
  

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

Menée in vitro et in vivo, cette étude évalue l'activité d'un inhibiteur de gamma secrétase, MRK-003, en combinaison avec la gemcitabine pour le traitement d'un adénocarcinome canalaire du pancréas

• The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude évalue l'activité d'un inhibiteur de gamma secrétase, MRK-003, en combinaison avec la gemcitabine pour le traitement d'un adénocarcinome canalaire du pancréas

  “The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models”

  • Mizuma, Masamichi;Rasheed, Zeshaan A;Yabuuchi, Shinichi;Omura, Noriyuki;Campbell, Nathaniel R.;de Wilde, Roeland F;De Oliveira, Elizabeth;Zhang, Qing;Puig, Oscar;Matsui, William;Hidalgo, Manuel;Maitra, Anirban;Rajeshkumar, N.V

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, with most patients facing an adverse clinical outcome. Aberrant Notch pathway activation has been implicated in the initiation and progression of PDAC, specifically the aggressive phenotype of the disease. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts to determine whether pharmacological targeting of Notch pathway could inhibit PDAC growth and potentiate gemcitabine sensitivity. MRK-003, a potent and selective γ-secretase inhibitor, treatment is effective against PDAC as evidenced by the down-regulation of nuclear Notch1 intracellular domain (N1ICD), inhibition of anchorage independent growth, and reduction of tumor-initiating cells capable of extensive self-renewal. Pre-treatment of PDAC cells with MRK-003 in cell culture significantly inhibited the subsequent engraftment in immunocompromised mice. MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) PDAC ...

  
  

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

Mené sur 37 patients atteints d'un myélome multiple ou d'un lymphome réfractaire et/ou récidivant, cet essai de phase I évalue l'activité antitumorale et la toxicité du carfilzomib, un inhibiteur sélectif du protéasome

• A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Mené sur 37 patients atteints d'un myélome multiple ou d'un lymphome réfractaire et/ou récidivant, cet essai de phase I évalue l'activité antitumorale et la toxicité du carfilzomib, un inhibiteur sélectif du protéasome

  “A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma”

  • Alsina, Melissa;Trudel, Suzanne;Furman, Richard R.;Rosen, Peter J.;O'Connor, Owen A.;Comenzo, Raymond L.;Wong, Alvin F.;Kunkel, Lori A.;Molineaux, Christopher J.;Goy, Andre

  Purpose:Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma (MM). The objectives of this phase 1 study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies. Experimental Design:Carfilzomib (doses ranging from 1.2-27 mg/m2) was administered intravenously on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n=37) was followed by a dose-expansion phase (n=11) that comprised 2 cohorts (carfilzomib or carfilzomib + dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m2 during the first week (Days 1, 2) and then escalated to 27 mg/m2 thereafter. Results:A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events (AEs) were manageable ...

  
  

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

Mené sur 39 patients atteints d'un lymphome récidivant à cellules B, cet essai de phase I évalue un conjugué anticorps-médicament ciblant CD19, SAR3419

• Phase I Multidose-Escalation Study of the Anti-CD19 Maytansinoid Immunoconjugate SAR3419 Administered by Intravenous Infusion Every 3 Weeks to Patients With Relapsed/Refractory B-Cell Lymphoma
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 39 patients atteints d'un lymphome récidivant à cellules B, cet essai de phase I évalue un conjugué anticorps-médicament ciblant CD19, SAR3419

  “Phase I Multidose-Escalation Study of the Anti-CD19 Maytansinoid Immunoconjugate SAR3419 Administered by Intravenous Infusion Every 3 Weeks to Patients With Relapsed/Refractory B-Cell Lymphoma”

  • Younes, Anas;Kim, Stella;Romaguera, Jorge;Copeland, Amanda;Farial, Silvana de Castro;Kwak, Larry W.;Fayad, Luis;Hagemeister, Frederick;Fanale, Michelle;Neelapu, Sattva;Lambert, John M.;Morariu-Zamfir, Rodica;Payrard, Sandrine;Gordon, Leo I.

  Purpose We determine the maximum-tolerated dose (MTD), pharmacokinetics, safety, and preliminary efficacy of SAR3419, an antibody-drug conjugate targeting CD19, in a first-in-man phase I clinical trial in patients with relapsed lymphoma.Patients and Methods Patients with relapsed CD19+ B-cell lymphoma were treated with escalating doses of SAR3419 given by intravenous infusion once every 21 days.Results Thirty-nine patients were treated on seven dose levels ranging from 10 to 270 mg/m2. The median number of prior treatment regimens was four (range, 1 to 9), and 11 patients had prior autologous or allogeneic stem-cell transplantation. The dose-limiting toxicities were reversible severe blurred vision associated with microcystic epithelial corneal changes reported in six patients and neuropathy in one patient. The MTD was 160 mg/m2 once every 21 days. Hematologic and hepatic toxicities were predominantly grade 1 or 2 in severity. A total of 35 patients have completed at least two cycles ...

  
  

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

Menée sur un modèle murin transgénique de carcinome hépatocellulaire induit par le virus de l'hépatite B, cette étude évalue les effets d'un traitement antiplaquettaire au long cours sur le développement de la maladie

• Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée sur un modèle murin transgénique de carcinome hépatocellulaire induit par le virus de l'hépatite B, cette étude évalue les effets d'un traitement antiplaquettaire au long cours sur le développement de la maladie

  “Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B”

  • Sitia, Giovanni;Aiolfi, Roberto;Di Lucia, Pietro;Mainetti, Marta;Fiocchi, Amleto;Mingozzi, Francesca;Esposito, Antonio;Ruggeri, Zaverio M.;Chisari, Francis V.;Iannacone, Matteo;Guidotti, Luca G.

  Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-associated HCC involves both viral and host factors. The latter include a functionally inefficient CD8+ T-cell response that fails to clear the infection from the liver but sustains a chronic necroinflammatory process that contributes to the development of HCC. According to this scenario, amelioration of immune-mediated chronic liver injury may prevent HCC. Because platelets facilitate immune-mediated liver injury by promoting the hepatic accumulation of virus-specific CD8+ T cells, we evaluated the long-term consequences of antiplatelet therapy in an HBV transgenic mouse model of chronic immune-mediated necroinflammatory liver disease that progresses to HCC. Treatment with aspirin and clopidogrel during the chronic phase of the disease diminished the number of intrahepatic HBV-specific CD8+ T cells and HBV-nonspecific inflammatory cells, ...

  
  

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

Menée sur des lignées cellulaires, cette étude suggère qu'un traitement activant la voie de signalisation Notch1 représente une stratégie thérapeutique intéressante pour le traitement des patients atteints d'une tumeur stromale gastro-intestinale ayant développé une résistance à l'imatinib

• Anti-tumor effects of Notch pathway in Gastrointestinal Stromal Tumors
  • Carcinogenesis, sous presse, 2012 (résumé)
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  Menée sur des lignées cellulaires, cette étude suggère qu'un traitement activant la voie de signalisation Notch1 représente une stratégie thérapeutique intéressante pour le traitement des patients atteints d'une tumeur stromale gastro-intestinale ayant développé une résistance à l'imatinib

  “Anti-tumor effects of Notch pathway in Gastrointestinal Stromal Tumors”

  • Dumont, Amaury Gerard;Yang, Yanwen;Reynoso, David G;Katz, Daniela;Trent, Jonathan C;Hughes, Dennis

  Gastrointestinal Stromal Tumors (GISTs) are driven by gain-of-function mutations of KIT. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the Interstitial Cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In the present study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively active intracellular domain of Notch1 (ICN-1) expression potently induced growth arrest and ...

  
  

Mots clés : Appareil digestif (autre); Traitements (Traitements systémiques : découverte et développement)

Menées sur des lignées cellulaires, ces deux études identifient des mécanismes de résistance aux inhibiteurs de tyrosine kinase

• Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
  • Nature, sous presse, 2012 (résumé)
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  Menées sur des lignées cellulaires, ces deux études identifient des mécanismes de résistance aux inhibiteurs de tyrosine kinase

  “Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors”

  • Wilson, Timothy R.;Fridlyand, Jane;Yan, Yibing;Penuel, Elicia;Burton, Luciana;Chan, Emily;Peng, Jing;Lin, Eva;Wang, Yulei;Sosman, Jeff;Ribas, Antoni;Li, Jiang;Moffat, John;Sutherlin, Daniel P.;Koeppen, Hartmut;Merchant, Mark;Neve, Richard;Settleman, Jeff

  Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstreamcell-survival effectors—most notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK). Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma6 or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-‘addicted’ human cancer cell ...

  
  
• Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
  • Nature, sous presse, 2012 (résumé)
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  Menées sur des lignées cellulaires, ces deux études identifient des mécanismes de résistance aux inhibiteurs de tyrosine kinase

  “Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion”

  • Straussman, Ravid ; Morikawa, Teppei ; Shee, Kevin ; Barzily-Rokni, Michal ; Qian, Zhi Rong ; Du, Jinyan ; Davis, Ashli ; Mongare, Margaret M. ; Gould, Joshua ; Frederick, Dennie T. ; Cooper, Zachary A. ; Chapman, Paul B. ; Solit, David B. ; Ribas, Antoni ; Lo, Roger S. ; Flaherty, Keith T. ; Ogino, Shuji ; Wargo, Jennifer A. ; Golub, Todd R.

  Drug resistance presents a challenge to the treatment of cancer patients.Many studies have focusedoncell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour microenvironment confers innate resistance to therapy. Herewe developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance1–4. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogenactivated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)–AKT signalling pathways, and immediate resistance to RAF ...

  
  

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

Menée in vitro et in vivo, cette étude suggère que la kinase LIM représente une cible thérapeutique intéressante pour le traitement des cancers

• Pharmacological inhibition of LIM Kinase stabilizes microtubules and inhibits neoplastic growth
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude suggère que la kinase LIM représente une cible thérapeutique intéressante pour le traitement des cancers

  “Pharmacological inhibition of LIM Kinase stabilizes microtubules and inhibits neoplastic growth”

  • Prudent, Renaud;Vassal-Stermann, Emilie;Nguyen, Chi Hung;Pillet, Catherine;Martinez, Anne;Prunier, Chloe;Barette, Caroline;Soleilhac, Emmanuelle;Filhol, Odile;Beghin, Anne;Valdameri, Glaucio;Honore, Stephane;Aci-Seche, Samia;Grierson, David;Antonipillai, Juliana;Li, Rong;Di Pietro, Attilio;Dumontet, Charles;Braguer, Diane;Florent, Jean-Claude;Knapp, Stefan;Bernard, Ora;Lafanechere, Laurence

  The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM Kinase, which is the enzyme that phosphorylates and inactivates the actin depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, and inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM Kinase caused a microtubule stabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug resistant cancer cells that were resistant to conventional microtubule targeting agents. Our findings suggest that LIM Kinase functions as a signaling node that controls both actin and ...

  
  

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

Menée sur 49 patients atteints d'une tumeur solide de stade avancé, cette étude évalue l'acitivté antitumorale et la toxicité d'un inhibiteur de MEK, RO4987655

• Phase I Dose-escalation Study of the Safety, Pharmacokinetics and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumours
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Menée sur 49 patients atteints d'une tumeur solide de stade avancé, cette étude évalue l'acitivté antitumorale et la toxicité d'un inhibiteur de MEK, RO4987655

  “Phase I Dose-escalation Study of the Safety, Pharmacokinetics and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumours”

  • Leijen, Suzanne;Middleton, Mark R.;Tresca, Patricia;Kraeber-Bodere, Francoise;Dieras, Veronique;Scheulen, Max;Gupta, Avinash;Lopez-Valverde, Vanesa;Xu, Zhi-Xin;Rueger, Ruediger;Tessier, Jean J. L.;Shochat, Eliezer;Blotner, Steve;Meresse Naegelen, Valerie;Schellens, Jan H.M.;Eberhardt, Wilfried Ernst Erich

  Purpose: This Phase I study of the MEK inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK)/pharmacodynamics (PD) profile and anti-tumour activity in patients with advanced solid tumours. Patients and Methods: An initial dose-escalation was performed using a once-daily (QD) dosing schedule, with oral RO4987655 administered at doses of 1.0-2.5 mg QD over 28 consecutive days in 4-week cycles. Doses were then escalated to 3.0-21.0 mg (total daily dose [TDD]) using a twice-daily (BID) dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n=1) and elevated creatine phosphokinase (n=3). The MTD was 8.5 mg BID (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 demonstrated dose-linearity and a half-life of ~4 hours. At the MTD, target inhibition, assessed by ...

  
  

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

Menée à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un anticorps monoclonal, OMP-18R5, ciblant la voie de signalisation Wnt

• Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un anticorps monoclonal, OMP-18R5, ciblant la voie de signalisation Wnt

  “Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors”

  • Gurney, Austin;Axelrod, Fumiko;Bond, Christopher J.;Cain, Jennifer;Chartier, Cecile;Donigan, Lucas;Fischer, Marcus;Chaudhari, Aurélie;Ji, May;Kapoun, Ann M.;Lam, Andrew;Lazetic, Sasha;Ma, Shirley;Mitra, Satyajit;Park, In-Kyung;Pickell, Kellie;Sato, Aaron;Satyal, Sanjeev;Stroud, Michelle;Tran, Hoang;Yen, Wan-Ching;Lewicki, John;Hoey, Timothy

  The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.

  
  

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

Mené sur 59 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue l'activité antitumorale et la toxicité de l'alisertib, un inhibiteur de la kinase Aurora A

• Phase 1 Pharmacokinetic/Pharmacodynamic Study of MLN8237 - An Investigational, Oral, Selective Aurora A Kinase Inhibitor - In Patients With Advanced Solid Tumors
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Mené sur 59 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue l'activité antitumorale et la toxicité de l'alisertib, un inhibiteur de la kinase Aurora A

  “Phase 1 Pharmacokinetic/Pharmacodynamic Study of MLN8237 - An Investigational, Oral, Selective Aurora A Kinase Inhibitor - In Patients With Advanced Solid Tumors”

  • Cervantes, Andres;Elez, Elena;Roda, Desamparados;Ecsedy, Jeffrey A.;Macarulla, Teresa;Venkatakrishnan, Karthik;Rosello, Susana;Andreu, Jordi;Jung, JungAh;Sanchis-Garcia, Juan Manuel;Piera, Adelaida;Blasco, Inma;Manos, Laura;Perez-Fidalgo, Alejandro;Fingert, Howard;Baselga, Jose;Tabernero, Josep

  Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anti-cancer drug development. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors. Experimental Design: Patients received MLN8237 once daily (QD) or twice daily (BID) for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLTs) and the MTD for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed. Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg BID and 50 mg QD, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was ...

  
  

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

Cet article passe en revue les perspectives offertes par des anticorps monoclonaux anti CD39 pour le traitement des cancers

• ENTPD1/CD39 is a promising therapeutic target in oncology
  • Oncogene, sous presse, 2012 (résumé)
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  Cet article passe en revue les perspectives offertes par des anticorps monoclonaux anti CD39 pour le traitement des cancers

  “ENTPD1/CD39 is a promising therapeutic target in oncology”

  • Bastid, J.;Cottalorda-Regairaz, A.;Alberici, G.;Bonnefoy, N.;Eliaou, J. F.;Bensussan, A.

  Regulatory T cells (Tregs) are a subpopulation of CD4+ T cells that are essential for maintaining the homeostasis of the immune system, limiting self-reactivity and excessive immune responses against foreign antigens. In cancer, infiltrated Tregs inhibit the effector lymphocytes and create a favorable environment for the growth of the tumor. Although Tregs mediate immunosuppression through multiple, non-redundant, cell-contact dependent and independent mechanisms, a growing body of evidence suggests an important role for the CD39–CD73–adenosine pathway. CD39 ectonucleotidase is the rate-limiting enzyme of a cascade leading to the generation of suppressive adenosine that alters CD4 and CD8 T cell and natural killer cell antitumor activities. Here, we review the recent literature supporting CD39 as a promising therapeutic target in oncology. In vitro and in vivo experiments involving knockout models and surrogate inhibitors of CD39 provide evidence in support of the anticancer ...

  
  

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

Mené sur 60 patients atteints d'un cancer résécable du poumon non à petites cellules, cet essai néerlandais de phase II évalue, du point de vue de la toxicité et de la réponse pathologique, l'erlotinib en traitement néoadjuvant

• Tumor Response and Toxicity of Neoadjuvant Erlotinib in Patients With Early-Stage Non–Small-Cell Lung Cancer
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 60 patients atteints d'un cancer résécable du poumon non à petites cellules, cet essai néerlandais de phase II évalue, du point de vue de la toxicité et de la réponse pathologique, l'erlotinib en traitement néoadjuvant

  “Tumor Response and Toxicity of Neoadjuvant Erlotinib in Patients With Early-Stage Non–Small-Cell Lung Cancer”

  • Schaake, Eva E.;Kappers, Ingrid;Codrington, Henk E.;Valdés Olmos, Renato A.;Teertstra, Hendrik J.;van Pel, Renée;Burgers, Jacobus A.;van Tinteren, Harm;Klomp, Houke M.

  Purpose The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non–small-cell lung cancer (NSCLC).Patients and Methods This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simon’s minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic ...

  
  

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

Mené sur 1 090 patients atteints d'un cancer non épidermoïde du poumon non à petites cellules de stade avancé, cet essai de phase III évalue, du point de vue de la survie globale, l'ajout de motesanib à un traitement combinant carboplatine et paclitaxel

• International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 1 090 patients atteints d'un cancer non épidermoïde du poumon non à petites cellules de stade avancé, cet essai de phase III évalue, du point de vue de la survie globale, l'ajout de motesanib à un traitement combinant carboplatine et paclitaxel

  “International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1”

  • Scagliotti, Giorgio V.;Vynnychenko, Ihor;Park, Keunchil;Ichinose, Yukito;Kubota, Kaoru;Blackhall, Fiona;Pirker, Robert;Galiulin, Rinat;Ciuleanu, Tudor-Eliade;Sydorenko, Oleksandr;Dediu, Mircea;Papai-Szekely, Zsolt;Banaclocha, Natividad Martinez;McCoy, Sheryl;Yao, Bin;Hei, Yong-jiang;Galimi, Francesco;Spigel, David R.

  Purpose We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non–small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma.Patients and Methods Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m2) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS.Results A total of 1,090 patients with ...

  
  
• Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC): Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  Mené sur 1 090 patients atteints d'un cancer non épidermoïde du poumon non à petites cellules de stade avancé, cet essai de phase III évalue, du point de vue de la survie globale, l'ajout de motesanib à un traitement combinant carboplatine et paclitaxel

  “Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC): Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)”

  • Morgensztern, Daniel ; Herbst, Roy S.

  
  

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

Mené sur 188 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase II compare, du point de vue de la survie sans progression et de la toxicité, le dacomitinib et l'erlotinib en fonction de la présence de mutations des gènes EGFR et/ou KRAS

• Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 188 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase II compare, du point de vue de la survie sans progression et de la toxicité, le dacomitinib et l'erlotinib en fonction de la présence de mutations des gènes EGFR et/ou KRAS

  “Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer”

  • Ramalingam, Suresh S.;Blackhall, Fiona;Krzakowski, Maciej;Barrios, Carlos H.;Park, Keunchil;Bover, Isabel;Seog Heo, Dae;Rosell, Rafael;Talbot, Denis C.;Frank, Richard;Letrent, Stephen P.;Ruiz-Garcia, Ana;Taylor, Ian;Liang, Jane Q.;Campbell, Alicyn K.;O'Connell, Joseph;Boyer, Michael

  Purpose This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non–small-cell lung cancer (NSCLC).Patients and Methods Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily.Results One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib ...

  
  
• Timing of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Patients With Lung Cancer With EGFR Mutations
  • Journal of Clinical Oncology, sous presse, 2012 (commentaire)
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  Mené sur 188 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase II compare, du point de vue de la survie sans progression et de la toxicité, le dacomitinib et l'erlotinib en fonction de la présence de mutations des gènes EGFR et/ou KRAS

  “Timing of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Patients With Lung Cancer With EGFR Mutations”

  • Moran, Teresa ; Sequist, Lecia V.

  A 45-year-old never-smoking woman was referred for a consultation about additional management of her recently diagnosed stage IV lung adenocarcinoma. The diagnosis was suspected on the basis of a chest X-ray (CXR) obtained for additional evaluation of dry cough and dyspnea. The CXR and subsequent computed tomography (CT) –scan revealed a left upper lobe mass and multiple, smaller bilateral nodules. The diagnosis was confirmed with percutaneous CT-guided fine-needle aspiration and 20-gauge core needle biopsy of the left upper lobe mass, which revealed adenocarcinoma. Immunohistochemical stains were positive for CK7 and negative for CK20 and thyroid transcription factor-1, consistent with pulmonary origin. Staging evaluation including positron emission tomography-CT confirmed the CXR findings, but no disease was detected outside the thorax. EGFR, KRAS, and ALK genotyping had been ordered and was still pending at the time of the consultation. Because of the symptoms, the patient and ...

  
  
• Another Innovation at Journal of Clinical Oncology
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  Mené sur 188 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase II compare, du point de vue de la survie sans progression et de la toxicité, le dacomitinib et l'erlotinib en fonction de la présence de mutations des gènes EGFR et/ou KRAS

  “Another Innovation at Journal of Clinical Oncology”

  • Cannistra, Stephen A.

  
  

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

Mené sur 281 patients atteints d'un cancer avancé du pancréas, cet essai allemand de phase III évalue deux protocoles d'administration séquentielle d'un traitement combinant capecitabine, erlotinib et gemcitabine

• Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104)
  • Gut, sous presse, 2012 (résumé)
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  Mené sur 281 patients atteints d'un cancer avancé du pancréas, cet essai allemand de phase III évalue deux protocoles d'administration séquentielle d'un traitement combinant capecitabine, erlotinib et gemcitabine

  “Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104)”

  • Heinemann, Volker;Vehling-Kaiser, Ursula;Waldschmidt, Dirk;Kettner, Erika;Märten, Angela;Winkelmann, Cornelia;Klein, Stefan;Kojouharoff, Georgi;Gauler, Thomas C;Fischer von Weikersthal, Ludwig;Clemens, Michael R;Geissler, Michael;Greten, Tim F;Hegewisch-Becker, Susanna;Rubanov, Oleg;Baake, Gerold;Höhler, Thomas;Ko, Yon D;Jung, Andreas;Neugebauer, Sascha;Boeck, Stefan

  Objective AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine.Methods 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients.Results Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in ...

  
  

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

Cet article passe en revue les travaux concernant les effets, sur la progression de la maladie et la survie, de traitements visant à prévenir les complications osseuses chez les patients atteints de cancer

• Effects of Bone-Targeted Agents on Cancer Progression and Mortality
  • Journal of the National Cancer Institute, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux concernant les effets, sur la progression de la maladie et la survie, de traitements visant à prévenir les complications osseuses chez les patients atteints de cancer

  “Effects of Bone-Targeted Agents on Cancer Progression and Mortality”

  • Coleman, Robert;Gnant, Michael;Morgan, Gareth;Clezardin, Philippe

  Bone-targeted treatments with bisphosphonates and denosumab, which reduce bone resorption, are known to reduce the risk of skeletal complications and prevent treatment-induced bone loss in patients with malignant bone disease. Additionally, these drugs may modify the course of bone destruction via inhibitory effects on the “vicious cycle” of growth factor and cytokine signaling between tumor and bone cells within the bone marrow microenvironment. Effects of the drugs on the stem cell niche, direct effects on the cancer cells, and immune modulation may also contribute. In early-stage (stages I, II, and III) breast cancer, treatment with the bisphosphonate zoledronic acid has shown improvements in disease-free and overall survival. Improved survival was particularly notable in women with established menopause at diagnosis and in premenopausal women with endocrine-responsive disease who received treatment with goserelin, which suppresses ovarian function by inhibiting the production ...

  
  

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

Mené sur 410 patients atteints d'un carcinome épidermoïde de la tête et du cou à risque élevé de récidive et traités par résection chirurgicale (durée médiane de suivi : 9,4 ans), cet essai randomisé de phase III évalue, du point de vue du contrôle loco-régional de la maladie et de la survie globale à 10 ans, l'intérêt de combiner une chimiothérapie concomitante par cisplatine avec une radiothérapie

• Long-term Follow-up of the RTOG 9501/Intergroup Phase III Trial: Postoperative Concurrent Radiation Therapy and Chemotherapy in High-Risk Squamous Cell Carcinoma of the Head and Neck
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Mené sur 410 patients atteints d'un carcinome épidermoïde de la tête et du cou à risque élevé de récidive et traités par résection chirurgicale (durée médiane de suivi : 9,4 ans), cet essai randomisé de phase III évalue, du point de vue du contrôle loco-régional de la maladie et de la survie globale à 10 ans, l'intérêt de combiner une chimiothérapie concomitante par cisplatine avec une radiothérapie

  “Long-term Follow-up of the RTOG 9501/Intergroup Phase III Trial: Postoperative Concurrent Radiation Therapy and Chemotherapy in High-Risk Squamous Cell Carcinoma of the Head and Neck”

  • Cooper, Jay S.;Zhang, Qiang;Pajak, Thomas F.;Forastiere, Arlene A.;Jacobs, John;Saxman, Scott B.;Kish, Julie A.;Kim, Harold E.;Cmelak, Anthony J.;Rotman, Marvin;Lustig, Robert;Ensley, John F.;Thorstad, Wade;Schultz, Christopher J.;Yom, Sue S.;Ang, K. Kian

  Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months, the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head-and-neck carcinomas. With a minimum of 10 years of follow-up potentially now available for all patients, these results are updated here to examine long-term outcomes. A total of 410 analyzable patients who had high-risk resected head-and-neck cancers were prospectively randomized to receive either radiation therapy (RT: 60 Gy in 6 weeks) or identical RT plus cisplatin, 100 mg/m2 i.v. on days 1, 22, and 43 (RT + CT). At 10 years, the local-regional failure rates were 28.8% vs 22.3% (P=.10), disease-free survival was 19.1% vs 20.1% (P=.25), and overall survival was 27.0% vs 29.1% (P=.31) for patients treated by RT vs RT + CT, respectively. In the unplanned subset analysis limited ...

  
  

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

Cette revue systématique de la littérature (357 articles publiés entre 2005 et 2009) évalue le degré de conformité, vis-à-vis des recommandations CONSORT, des publications d'essais cliniques randomisés évaluant des traitements anticancéreux

• Quality of Reporting of Modern Randomized Controlled Trials in Medical Oncology: A Systematic Review
  • Journal of the National Cancer Institute, sous presse, 2012 (résumé)
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  Cette revue systématique de la littérature (357 articles publiés entre 2005 et 2009) évalue le degré de conformité, vis-à-vis des recommandations CONSORT, des publications d'essais cliniques randomisés évaluant des traitements anticancéreux

  “Quality of Reporting of Modern Randomized Controlled Trials in Medical Oncology: A Systematic Review”

  • Péron, Julien;Pond, Gregory R;Gan, Hui K;Chen, Eric X;Almufti, Roula;Maillet, Denis;You, Benoit

  Background The Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in the mid-1990s for the explicit purpose of improving clinical trial reporting. However, there is little information regarding the adherence to CONSORT guidelines of recent publications of randomized controlled trials (RCTs) in oncology.Methods All phase III RCTs published between 2005 and 2009 were reviewed using an 18-point overall quality score for reporting based on the 2001 CONSORT statement. Multivariable linear regression was used to identify features associated with improved reporting quality. To provide baseline data for future evaluations of reporting quality, RCTs were also assessed according to the 2010 revised CONSORT statement. All statistical tests were two-sided.Results A total of 357 RCTs were reviewed. The mean 2001 overall quality score was 13.4 on a scale of 0–18, whereas the mean 2010 overall quality score was 19.3 on a scale of 0–27. The overall RCT reporting ...

  
  

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

Cet article présente les recommandations d'un groupe d'experts pour améliorer les recherches visant à réduire les toxicités relatives aux traitements des cancers

• Reducing the toxicity of cancer therapy: recognizing needs, taking action
  • Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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  Cet article présente les recommandations d'un groupe d'experts pour améliorer les recherches visant à réduire les toxicités relatives aux traitements des cancers

  “Reducing the toxicity of cancer therapy: recognizing needs, taking action”

  • Cleeland, Charles S.;Allen, Jeff D.;Roberts, Samantha A.;Brell, Joanna M.;Giralt, Sergio A.;Khakoo, Aarif Y.;Kirch, Rebecca A.;Kwitkowski, Virginia E.;Liao, Zhongxing;Skillings, Jamey

  Our understanding of the biology of cancer and the application of this knowledge to cancer treatment has greatly outpaced what we know of the biology underlying the symptoms and toxic effects that therapies produce. These adverse effects of therapy cause substantial discomfort and distress to patients and their families, limit treatment tolerability and can persist indefinitely in post-treatment survivorship. Despite these concerns, little research effort is targeted at documenting the nature of these effects. Similarly, limited efforts are being made in the drug-development arena to identify or develop treatments that might prevent or reduce toxicities. A panel of clinicians and researchers as well as representatives from advocacy groups, federal agencies and the pharmaceutical industry was convened to identify gaps in cancer treatment toxicity research and to provide direction for future action. With an emphasis on coordinating multidisciplinary efforts, this panel has presented a ...

  
  

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