Traitements

Cette étude montre que des nanoparticules d'or conjuguées à un ligand des protéines SUMO peut inhiber les interactions protéiques impliquant les chaînes de poly-SUMO et augmenter l'efficacité de la radiothérapie

• Gold nanoparticles as a platform for creating a multivalent poly-SUMO chain inhibitor that also augments ionizing radiation
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cette étude montre que des nanoparticules d'or conjuguées à un ligand des protéines SUMO peut inhiber les interactions protéiques impliquant les chaînes de poly-SUMO et augmenter l'efficacité de la radiothérapie

  “Gold nanoparticles as a platform for creating a multivalent poly-SUMO chain inhibitor that also augments ionizing radiation”

  • Li, Yi-Jia;Perkins, Angela L.;Su, Yang;Ma, Yuelong;Colson, Loren;Horne, David A.;Chen, Yuan

  Protein-protein interactions mediated by ubiquitin-like (Ubl) modifications occur as mono-Ubl or poly-Ubl chains. Proteins that regulate poly-SUMO (small ubiquitin-like modifier) chain conjugates play important roles in cellular response to DNA damage, such as those caused by cancer radiation therapy. Additionally, high atomic number metals, such as gold, preferentially absorb much more X-ray energy than soft tissues, and thus augment the effect of ionizing radiation when delivered to cells. In this study, we demonstrate that conjugation of a weak SUMO-2/3 ligand to gold nanoparticles facilitated selective multivalent interactions with poly-SUMO-2/3 chains leading to efficient inhibition of poly-SUMO-chain-mediated protein-protein interactions. The ligand-gold particle conjugate significantly sensitized cancer cells to radiation but was not toxic to normal cells. This study demonstrates a viable approach for selective targeting of poly-Ubl chains through multivalent interactions ...

  
  

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

Menée à partir des données des registres américains du cancer sur la période 1988 - 2007, cette étude rétrospective montre que l'utilisation de la radiothérapie pour traiter des tumeurs malignes primitives de la trachée semble améliorer la survie globale des patients (258 cas ; durée médiane de suivi : 60 mois)

• The Use of Radiation Therapy Appears to Improve Outcome in Patients with Malignant Primary Tracheal Tumors: A SEER-Based Analysis
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée à partir des données des registres américains du cancer sur la période 1988 - 2007, cette étude rétrospective montre que l'utilisation de la radiothérapie pour traiter des tumeurs malignes primitives de la trachée semble améliorer la survie globale des patients (258 cas ; durée médiane de suivi : 60 mois)

  “The Use of Radiation Therapy Appears to Improve Outcome in Patients with Malignant Primary Tracheal Tumors: A SEER-Based Analysis”

  • Xie, Liyi;Fan, Min;Sheets, Nathan C.;Chen, Ronald C.;Jiang, Guo-Liang;Marks, Lawrence B.

  To conduct a matched pair analysis assessing the impact of radiotherapy (RT) in patients with resectable and unresectable primary malignant tracheal tumors using Surveillance, Epidemiology and End Results (SEER) database. The SEER registry was used to identify every patient (or “case”) who received RT between 1988 and 2007 for primary malignant tracheal tumors, and to search for corresponding “controls” (not treated with RT), with the same prognostic and treatment factors (surgery on the trachea, disease extension, histology, and gender). Overall survival (OS) was calculated with the Kaplan-Meier methods. Results of OS and cumulative incidence of death from tracheal cancer in the cases and controls, and in various subsets, were compared using log–rank and Gray’s tests. Two hundred fifty-eight patients who received RT were identified, and 78 of these had appropriate matched controls identified, forming the basis of this analysis. In the 78 (+RT) cases, the median follow-up ...

  
  

Mots clés : Voies aérodigestives supérieures; Traitements (Traitements localisés : applications cliniques)

Menée sur 252 patientes atteintes d'un cancer de l'endomètre de stade IA avec invasion myométriale et ayant subi une hystérectomie, cette étude évalue la toxicité et l'efficacité d'un traitement postopératoire par brachythérapie vaginale, du point de vue de la survie globale et de la survie sans récidive à 5 ans

• Clinical Outcomes in International Federation of Gynecology and Obstetrics Stage IA Endometrial Cancer with Myometrial Invasion Treated with or Without Postoperative Vaginal Brachytherapy
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur 252 patientes atteintes d'un cancer de l'endomètre de stade IA avec invasion myométriale et ayant subi une hystérectomie, cette étude évalue la toxicité et l'efficacité d'un traitement postopératoire par brachythérapie vaginale, du point de vue de la survie globale et de la survie sans récidive à 5 ans

  “Clinical Outcomes in International Federation of Gynecology and Obstetrics Stage IA Endometrial Cancer with Myometrial Invasion Treated with or Without Postoperative Vaginal Brachytherapy”

  • Diavolitsis, V.;Rademaker, A.;Lurain, J.;Hoekstra, A.;Strauss, J.;Small, W.

  To assess the clinical outcomes of patients with Stage IA endometrial cancer with myometrial invasion treated with postoperative vaginal brachytherapy (VBT) with those who received no adjuvant therapy (NAT). All patients treated with hysterectomy for endometrial cancer at Northwestern Memorial Hospital between 1978 and 2005 were identified. Those patients with Stage IA disease with myometrial invasion who were treated with VBT alone or NAT were identified and included in the present analysis. Of 252 patients with Stage IA endometrial cancer with superficial (<50%) myometrial invasion who met the inclusion criteria, 169 underwent VBT and 83 received NAT. The median follow-up in the VBT and NAT groups was 103 and 61 months, respectively. In the VBT group, 56.8% had Grade 1, 37.9% had Grade 2, and 5.3% had Grade 3 tumors. In the NAT group, 75.9%, 20.5%, and 3.6% had Grade 1, 2, and 3 tumors, respectively. Lymphatic or vascular space invasion was noted in 12.4% of the VBT patients and ...

  
  

Mots clés : Utérus (autre); Traitements (Traitements localisés : applications cliniques)

Menée sur 111 patients présentant des tumeurs métastatiques du poumon traitées par radiothérapie stéréotaxique ablative, cette étude rétrospective évalue l'efficacité et la toxicité de doses de rayonnements ionisants adaptées au volume tumoral

• Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur 111 patients présentant des tumeurs métastatiques du poumon traitées par radiothérapie stéréotaxique ablative, cette étude rétrospective évalue l'efficacité et la toxicité de doses de rayonnements ionisants adaptées au volume tumoral

  “Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors”

  • Trakul, Nicholas;Chang, Christine N.;Harris, Jeremy;Chapman, Christopher;Rao, Aarti;Shen, John;Quinlan-Davidson, Sean;Filion, Edith J.;Wakelee, Heather A.;Colevas, A. Dimitrios;Whyte, Richard I.;Dieterich, Sonja;Maxim, Peter G.;Hristov, Dimitre;Tran, Phuoc;Le, Quynh-Thu;Loo, Billy W.;Diehn, Maximilian

  Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18–25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50–60 Gy in three to four fractions) (Group 2). The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p ...

  
  

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

Cet article évalue les données cliniques concernant l'utilisation de la radiothérapie dans le traitement local des métastases hépatiques et le traitement palliatif des métastases symptomatiques diffuses

• Radiotherapy for Liver Metastases: A Review of Evidence
  • International journal of radiation oncology, biology, physics, Vol. 82 (3), pp. 1047-1057, 2012 (résumé)
  Détails

  Fermer

  Cet article évalue les données cliniques concernant l'utilisation de la radiothérapie dans le traitement local des métastases hépatiques et le traitement palliatif des métastases symptomatiques diffuses

  “Radiotherapy for Liver Metastases: A Review of Evidence”

  • Høyer, Morten;Swaminath, Anand;Bydder, Sean;Lock, Michael;Méndez Romero, Alejandra;Kavanagh, Brian;Goodman, Karyn A.;Okunieff, Paul;Dawson, Laura A.

  Over the past decade, there has been an increasing use of radiotherapy (RT) for the treatment of liver metastases. Most often, ablative doses are delivered to focal liver metastases with the goal of local control and ultimately improving survival. In contrast, low-dose whole-liver RT may be used for the palliation of symptomatic diffuse metastases. This review examines the available clinical data for both approaches. The review found that RT is effective both for local ablation of focal liver metastases and for palliation of patients with symptomatic liver metastases. However, there is a lack of a high level of evidence from randomized clinical trials.

  
  

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

Menée sur 65 patientes atteintes d'un cancer du col de l'utérus ou de l'endomètre, cette étude prospective évalue la toxicité aiguë et retardée d'un traitement postopératoire par arc-thérapie avec modulation d'intensité

• Postoperative Intensity-Modulated Arc Therapy for Cervical and Endometrial Cancer: A Prospective Report on Toxicity
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur 65 patientes atteintes d'un cancer du col de l'utérus ou de l'endomètre, cette étude prospective évalue la toxicité aiguë et retardée d'un traitement postopératoire par arc-thérapie avec modulation d'intensité

  “Postoperative Intensity-Modulated Arc Therapy for Cervical and Endometrial Cancer: A Prospective Report on Toxicity”

  • Vandecasteele, Katrien;Tummers, Philippe;Makar, Amin;van Eijkeren, Marc;Delrue, Louke;Denys, Hannelore;Lambert, Bieke;Beerens, Anne-Sophie;Van den Broecke, Rudy;Lambein, Kathleen;Fonteyne, Valérie;De Meerleer, Gert

  To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m², weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. Regarding acute toxicity (n = 65), Grade 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of ...

  
  

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

Mené sur 75 patientes atteintes d'un cancer du sein HER2- et présentant des cellules tumorales circulantes surexprimant l'ARNm CK 19, cet essai de phase II évalue l'effet du trastuzumab sur le risque de récidive (durée médiane de suivi : 67,2 mois)

• Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK19 mRNA-positive circulating tumor cells: results of a randomized phase II study
  • Annals of Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 75 patientes atteintes d'un cancer du sein HER2- et présentant des cellules tumorales circulantes surexprimant l'ARNm CK 19, cet essai de phase II évalue l'effet du trastuzumab sur le risque de récidive (durée médiane de suivi : 67,2 mois)

  “Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK19 mRNA-positive circulating tumor cells: results of a randomized phase II study”

  • Georgoulias, V.;Bozionelou, V.;Agelaki, S.;Perraki, M.;Apostolaki, S.;Kallergi, G.;Kalbakis, K.;Xyrafas, A.;Mavroudis, D.

  Background: Since the detection of circulating tumor cells (CTCs), which express that human epidermal growth factor receptor 2 (HER2) is an adverse prognostic factor in early breast cancer patients, we investigated the effect of trastuzumab on patients' clinical outcome.Patients and methods: Seventy-five women with HER2-negative breast cancer and detectable CK19 messenger RNA (mRNA)-positive CTCs before and after adjuvant chemotherapy were randomized to receive either trastuzumab (n = 36) or observation (n = 39). CK19 mRNA-positive CTCs were detected by RT-PCR and double-stained CK-positive/HER2-positive cells by immunofluorescence. The primary end point was the 3-year disease-free survival rate.Results: Fifty-one (89%) of the 57 analyzed patients had HER2-expressing CTCs. After trastuzumab administration, 27 of 36 (75%) women became CK19 mRNA negative compared with 7 of 39 (17.9%) in the observation arm (P = 0.001). After a median follow-up time of 67.2 months, 4 (11%) and 15 (38%) ...

  
  

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

Mené sur 31 patients atteints d'un sarcome de stade avancé, cet essai de phase I évalue l'ajout de flavopiridol, un inhibiteur de kinases dépendantes des cyclines, à la doxorubicine

• The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and phase I clinical trial
  • Clinical Cancer Research, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 31 patients atteints d'un sarcome de stade avancé, cet essai de phase I évalue l'ajout de flavopiridol, un inhibiteur de kinases dépendantes des cyclines, à la doxorubicine

  “The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and phase I clinical trial”

  • Luke, Jason J;D'Adamo, David R;Dickson, Mark A;Keohan, Mary Louise;Carvajal, Richard D;Maki, Robert G;de Stanchina, Elisa;Musi, Elgilda;Singer, Samuel;Schwartz, Gary K.

  Purpose: Dysregulated cyclin-dependent kinases (CDKs) are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and performed a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. Experimental Design: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on 2 flavopiridol schedules; a 1 hour bolus and split dosing as a 30 minute bolus followed by a 4 hour infusion. Results: Pre-clinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour prior to flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in 2 schedules (90 mg/m2 bolus; 50 mg/m2 ...

  
  

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

Cet article passe en revue les perspectives offertes par des anticorps dirigés contre CTLA4, à l'exemple de l'ipilimumab, pour le traitement d'un cancer de la prostate

• Unmasking the immune recognition of prostate cancer with CTLA4 blockade
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les perspectives offertes par des anticorps dirigés contre CTLA4, à l'exemple de l'ipilimumab, pour le traitement d'un cancer de la prostate

  “Unmasking the immune recognition of prostate cancer with CTLA4 blockade”

  • Kwek, Serena S.;Cha, Edward;Fong, Lawrence

  Although cancer cells can be immunogenic, tumour progression is associated with the evasion of immunosurveillance, the promotion of tumour tolerance and even the production of pro-tumorigenic factors by immune cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) represents a crucial immune checkpoint, the blockade of which can potentiate anti-tumour immunity. CTLA4-blocking antibodies are now an established therapeutic approach for malignant melanoma, and clinical trials with CTLA4-specific antibodies in prostate cancer have also shown clinical activity. This treatment may provide insights into the targets that the immune system recognizes to drive tumour regression, and could potentially improve both outcome and toxicity for patients with prostate cancer.

  
  

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

Menée sur un modèle murin d'adénocarcinome canalaire du pancréas, cette étude identifie des mécanismes sous-jacents à un traitement combinant gemcitabine et nab-paclitaxel, une formulation de paclitaxel fixé à l'albumine

• nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer
  • Cancer Discovery, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur un modèle murin d'adénocarcinome canalaire du pancréas, cette étude identifie des mécanismes sous-jacents à un traitement combinant gemcitabine et nab-paclitaxel, une formulation de paclitaxel fixé à l'albumine

  “nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer”

  • Frese, Kristopher K.;Neesse, Albrecht;Cook, Natalie;Bapiro, Tashinga E.;Lolkema, Martijn P.;Jodrell, Duncan I.;Tuveson, David A.

  Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that ...

  
  

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

Mené sur 73 patientes atteintes d'un cancer de l'ovaire résistant au platine, cet essai de phase II évalue le sunitinib du point de vue du taux de réponse objective

• A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monother
  • Annals of Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 73 patientes atteintes d'un cancer de l'ovaire résistant au platine, cet essai de phase II évalue le sunitinib du point de vue du taux de réponse objective

  “A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monother”

  • Baumann, K. H.;du Bois, A.;Meier, W.;Rau, J.;Wimberger, P.;Sehouli, J.;Kurzeder, C.;Hilpert, F.;Hasenburg, A.;Canzler, U.;Hanker, L. C.;Hillemanns, P.;Richter, B.;Wollschlaeger, K.;Dewitz, T.;Bauerschlag, D.;Wagner, U.

  Background: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting.Material and methods: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously).Results: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to ...

  
  

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

Menée sur des lignées cellulaires de mélanome présentant une mutation V600E ou V600K du gène BRAF, cette étude identifie des mutations du gène MEK1 ou NRAS associées à l'apparition d'une résistance à un inhibiteur de BRAF et montre que la combinaison de deux molécules permet de surmonter cette résistance

• Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur des lignées cellulaires de mélanome présentant une mutation V600E ou V600K du gène BRAF, cette étude identifie des mutations du gène MEK1 ou NRAS associées à l'apparition d'une résistance à un inhibiteur de BRAF et montre que la combinaison de deux molécules permet de surmonter cette résistance

  “Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations”

  • Greger, James;Eastman, Stephen;Zhang, Vivian;Bleam, Maureen R;Hughes, Ashley;Smitheman, Kimberly N.;Dickerson, Scott;Laquerre, Sylvie;Liu, Li;Gilmer, Tona M

  Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAFV600E and the YUSIT1 BRAFV600K melanoma cell lines. These clones also showed reduced sensitivity to the allosteric MEK inhibitor GSK1120212 (trametinib). Genetic characterization of these clones identified an in-frame deletion in MEK1 (MEK1K59del) or NRAS mutation (NRASQ61K and/or NRASA146T) with and without MEK1P387S in the BRAFV600E background and NRASQ61K in the BRAFV600K background. Stable knockdown of NRAS with short hairpin RNA partially restored GSK2118436 sensitivity in mutant NRAS clones, while expression of NRASQ61K or NRASA146T in the A375 parental cells decreased sensitivity to GSK2118436. Similarly, ...

  
  

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

Mené sur 78 patients atteints d'un lymphome de Hodgkin classique, cet essai de phase II évalue l'ajout de rituximab à un protocole de chimiothérapie ABVD (doxorubicine, bléomycine, vinblastine et dacarbazine)

• Phase II study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma
  • Blood, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 78 patients atteints d'un lymphome de Hodgkin classique, cet essai de phase II évalue l'ajout de rituximab à un protocole de chimiothérapie ABVD (doxorubicine, bléomycine, vinblastine et dacarbazine)

  “Phase II study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma”

  • Younes, Anas;Oki, Yasuhiro;McLaughlin, Peter;Copeland, Amanda R.;Goy, Andre;Pro, Barbara;Feng, Lei;Yuan, Ying;Chuang, Hubert H.;Macapinlac, Homer A.;Hagemeister, Frederick;Romaguera, Jorge;Samaniego, Felipe;Fanale, Michelle A.;Shabib Dabaja, Bouthaina;Rodriguez, Maria A.;Dang, Nam;Kwak, Larry W.;Neelapu, Sattva S.;Fayad, Luis E.

  We evaluated the efficacy and safety of rituximab in combination with standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with classical Hodgkin lymphoma (cHL). In this phase II study, patients with chemotherapy naive advanced stage cHL were treated with rituximab 375 mg/m2 weekly for six weeks and standard ABVD for six cycles. The primary outcome is event free survival (EFS) at five years. 85 patients were enrolled, of whom 78 patients were eligible. With a median follow up duration of 68 months (range 26-110), and based on an intent-to-treat analysis, the five-year EFS and overall survival (OS) rates were 83% and 96%, respectively. The five-year EFS for patients with stage III/IV was 82%. Furthermore, the five-year EFS for patients with International Prognostic Score (IPS) of 0 to 2 was 88% and for those with IPS score of > 2 was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutropenia (23%), fatigue (9%), and nausea (8%). ...

  
  

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

Mené sur 118 patients atteints d'une leucémie myéloïde chronique en phase chronique, cet essai de phase I/II évalue la toxicité et l'efficacité du bosutinib après l'échec d'un traitement à l'imatinib, puis au dasatinib et/ou au nilotinib

• Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure
  • Blood, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 118 patients atteints d'une leucémie myéloïde chronique en phase chronique, cet essai de phase I/II évalue la toxicité et l'efficacité du bosutinib après l'échec d'un traitement à l'imatinib, puis au dasatinib et/ou au nilotinib

  “Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure”

  • Khoury, H. Jean;Cortes, Jorge E.;Kantarjian, Hagop M.;Gambacorti-Passerini, Carlo B.;Baccarani, Michele;Kim, Dong-Wook;Zaritskey, Andrey;Countouriotis, Athena;Besson, Nadine;Leip, Eric;Kelly, Virginia;Brummendorf, Tim H.

  Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase I/II study evaluated the efficacy and safety of once-daily bosutinib 500 mg in patients with CML or acute lymphoblastic leukemia following resistance/intolerance to imatinib. The current analysis included 118 patients with chronic phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in 1 of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier–estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, ...

  
  

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

Menée in vitro et in vivo, cette étude identifie un mécanisme, lié à l'activation du récepteur EGFR, expliquant l'absence de réponse au vemurafenib des cellules de cancer du côlon présentant la mutation BRAF(V600E)

• Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
  • Nature, Vol. 483 (7388), pp. 100-103, 2012 (résumé)
  Détails

  Fermer

  Menée in vitro et in vivo, cette étude identifie un mécanisme, lié à l'activation du récepteur EGFR, expliquant l'absence de réponse au vemurafenib des cellules de cancer du côlon présentant la mutation BRAF(V600E)

  “Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR”

  • Prahallad, Anirudh;Sun, Chong;Huang, Sidong;Di Nicolantonio, Federica;Salazar, Ramon;Zecchin, Davide;Beijersbergen, Roderick L.;Bardelli, Alberto;Bernards, Rene

  Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation ...

  
  
• Translational medicine: Primed for resistance
  • Nature, Vol. 483 (7387), pp. 44-45, 2012 (commentaire)
  Détails

  Fermer

  Menée in vitro et in vivo, cette étude identifie un mécanisme, lié à l'activation du récepteur EGFR, expliquant l'absence de réponse au vemurafenib des cellules de cancer du côlon présentant la mutation BRAF(V600E)

  “Translational medicine: Primed for resistance”

  • Solit, David B. ; Janne, Pasi A.

  A drug for treating melanoma is ineffective in colorectal cancers that have the same causative mutation. Studies of how cells adapt to the drug reveal why this is so, and suggest combination therapies that may be more effective.

  
  

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

Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé AZD4547, un inhibiteur de l'activité kinase du récepteur du facteur de croissance des fibroblastes

• AZD4547: An orally bioavailable, potent and selective inhibitor of the Fibroblast Growth Factor Receptor tyrosine kinase family
  • Cancer Research, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé AZD4547, un inhibiteur de l'activité kinase du récepteur du facteur de croissance des fibroblastes

  “AZD4547: An orally bioavailable, potent and selective inhibitor of the Fibroblast Growth Factor Receptor tyrosine kinase family”

  • Gavine, Paul R;Mooney, Lorraine;Kilgour, Elaine;Thomas, Andrew P;Al-Kadhimi, Katherine;Beck, Sarah;Rooney, Claire;Coleman, Tanya;Baker, Dawn;Mellor, Martine J;Brooks, A Nigel;Klinowska, Teresa

  The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small molecule FGF-receptor (FGFR) kinase inhibitors are currently in clinical development, however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here we report the pharmacological profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2 and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR related effects were observed, ...

  
  

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

Cet article passe en revue les stratégies de recherche susceptibles d'identifier les mécanismes de résistance à des thérapies ciblées

• Circumventing Cancer Drug Resistance in the Era of Personalized Medicine
  • Cancer Discovery, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les stratégies de recherche susceptibles d'identifier les mécanismes de résistance à des thérapies ciblées

  “Circumventing Cancer Drug Resistance in the Era of Personalized Medicine”

  • Garraway, Levi A.;Jänne, Pasi A.

  All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance. Experimental approaches that can help predict the eventual clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, are rapidly identifying novel resistance mechanisms. In this review, we provide a historical background on drug resistance and a framework for understanding the common ways by which cancers develop resistance to targeted therapies. We further discuss advantages and disadvantages of experimental strategies that can be used to identify drug resistance mechanism(s).Significance: Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer. We provide a summary of current knowledge on drug resistance mechanisms and ...

  
  

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

Cet article passe en revue les travaux récents sur le développement d'inhibiteurs de mTOR pour le traitement de cancers gynécologiques

• Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer
  • Cancer treatment reviews, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les travaux récents sur le développement d'inhibiteurs de mTOR pour le traitement de cancers gynécologiques

  “Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer”

  • Diaz-Padilla, Ivan;Duran, Ignacio;Clarke, Blaise A.;Oza, Amit M.

  Advanced recurrent gynecological malignancies have a poor prognosis despite systemic treatment, which is usually cytotoxic chemotherapy. Responses are generally short-lived and more effective treatments are needed. Rationally designed molecularly targeted therapy is an emerging and important option in this setting. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway with a critical role in controlling cancer cellular growth, metabolism and cell cycle progression. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including ovarian, endometrial and cervical cancer. Early clinical studies of first-generation mTOR inhibitors have shown promising clinical activity in endometrial cancer. However, the molecular basis of sensitivity and resistance to these agents remains largely unknown. In this review, we will update the clinical and biological data underlying the ...

  
  

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

Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation du facteur de croissance des fibroblastes pour le traitement des cancers

• Fibroblast growth factor signaling: a new therapeutic opportunity in cancer
  • Clinical Cancer Research, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation du facteur de croissance des fibroblastes pour le traitement des cancers

  “Fibroblast growth factor signaling: a new therapeutic opportunity in cancer”

  • Brooks, A Nigel;Kilgour, Elaine;Smith, Paul D

  The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in normal organ, vascular and skeletal development. Deregulation of FGFR signaling through genetic modification or over-expression of the receptors (or their ligands) has been observed in numerous tumor settings, whilst the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of preclinical data demonstrates that inhibition of FGFR signaling can result in antiproliferative and/or pro-apoptotic effects, both in vitro and in vivo, thus confirming the validity of the FGF/FGFR axis as a potential therapeutic target. In the past, development of therapeutic approaches to target this axis has been hampered by our inability to develop FGFR selective agents. With the advent of a number of new modalities for selectively inhibiting FGF/FGFR signaling, we are now in a unique position to test and validate clinically the many hypotheses that have been ...

  
  

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

Cet article passe en revue les travaux récents sur l'immunogénicité tumorale et évalue les perspectives thérapeutiques offertes par ces connaissances

• The determinants of tumour immunogenicity
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les travaux récents sur l'immunogénicité tumorale et évalue les perspectives thérapeutiques offertes par ces connaissances

  “The determinants of tumour immunogenicity”

  • Blankenstein, Thomas;Coulie, Pierre G.;Gilboa, Eli;Jaffee, Elizabeth M.

  Many standard and targeted therapies, as well as radiotherapy, have been shown to induce an anti-tumour immune response, and immunotherapies rely on modulating the host immune system to induce an anti-tumour immune response. However, the immune response to such therapies is often reliant on the immunogenicity of a tumour. Tumour immunogenicity varies greatly between cancers of the same type in different individuals and between different types of cancer. So, what do we know about tumour immunogenicity and how might we therapeutically improve tumour immunogenicity? We asked four leading cancer immunologists around the world for their opinions on this important issue.

  
  

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

Mené sur 52 patientes atteintes d'un cancer inflammatoire du sein HER2+, cet essai français de phase II évalue la toxicité et l'efficacité d'un traitement néoadjuvant combinant bevacizumab, trastuzumab et chimiothérapie

• Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study
  • The Lancet Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 52 patientes atteintes d'un cancer inflammatoire du sein HER2+, cet essai français de phase II évalue la toxicité et l'efficacité d'un traitement néoadjuvant combinant bevacizumab, trastuzumab et chimiothérapie

  “Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study”

  • Pierga, Jean-Yves;Petit, Thierry;Delozier, Thierry;Ferrero, Jean-Marc;Campone, Mario;Gligorov, Joseph;Lerebours, Florence;Roché, Henri;Bachelot, Thomas;Charafe-Jauffret, Emmanuelle;Pavlyuk, Maria;Kraemer, Sandrine;Bidard, François-Clément;Viens, Patrice

  Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer; however, few data exist for this regimen in inflammatory breast cancer. In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ?18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1?4) and docetaxel, bevacizumab, and trastuzumab (cycles 5?8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological ...

  
  
• Inflammatory HER2-positive breast cancer
  • The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
  Détails

  Fermer

  Mené sur 52 patientes atteintes d'un cancer inflammatoire du sein HER2+, cet essai français de phase II évalue la toxicité et l'efficacité d'un traitement néoadjuvant combinant bevacizumab, trastuzumab et chimiothérapie

  “Inflammatory HER2-positive breast cancer”

  • Dirix, Luc Y. ; Vermeulen, Peter B.

  
  

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

Cette revue systématique de la littérature analyse les résultats d'essais cliniques randomisés ayant évalué des agents anti-angiogéniques pour le traitement d'un cancer du sein

• Controlling angiogenesis in breast cancer: A systematic review of anti-angiogenic trials
  • Cancer treatment reviews, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cette revue systématique de la littérature analyse les résultats d'essais cliniques randomisés ayant évalué des agents anti-angiogéniques pour le traitement d'un cancer du sein

  “Controlling angiogenesis in breast cancer: A systematic review of anti-angiogenic trials”

  • Mackey, John R.;Kerbel, Robert S.;Gelmon, Karen A.;McLeod, Deanna M.;Chia, Stephen K.;Rayson, Daniel;Verma, Sunil;Collins, Loretta L.;Paterson, Alexander H. G.;Robidoux, André;Pritchard, Kathleen I.

  Angiogenesis is critical for tumor growth and a promising therapeutic target. This review will summarize and analyze data from clinical trials of anti-angiogenic agents in the treatment of breast cancer (BC). A systematic search of PubMed and conference databases was performed to identify reports of randomized clinical trials investigating specific anti-angiogenic agents in the treatment of BC. Phase III trials in advanced BC have demonstrated a reduction in the risk of disease progression (22–52%), improved response rates and net improvements in progression-free survival of 1.2 to 5.5months, but no significant improvements in overall survival with the addition of bevacizumab to chemotherapy. Results of phase III trials in early breast cancer have been inconsistent. Bevacizumab-containing regimens have also been associated with higher overall adverse event rates compared to chemotherapy alone. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while ...

  
  

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

Mené sur 514 patientes atteintes d'un cancer du sein, cet essai de phase III évalue l'ajout de fulvestrant à l'anatrozole après une première récidive

• FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 514 patientes atteintes d'un cancer du sein, cet essai de phase III évalue l'ajout de fulvestrant à l'anatrozole après une première récidive

  “FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer”

  • Bergh, Jonas;Jönsson, Per-Ebbe;Lidbrink, Elisabet Kerstin;Trudeau, Maureen;Eiermann, Wolfgang;Brattström, Daniel;Lindemann, Justin P.O.;Wiklund, Fredrik;Henriksson, Roger

  Purpose To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer.Patients and Methods Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor– and/or progesterone receptor–positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP).Results In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus ...

  
  

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

Cet article passe en revue les travaux récents sur le rôle du denosumab dans le traitement des patients atteints d'un cancer de la prostate

• Role of denosumab in prostate cancer
  • Prostate Cancer and Prostatic Diseases, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les travaux récents sur le rôle du denosumab dans le traitement des patients atteints d'un cancer de la prostate

  “Role of denosumab in prostate cancer”

  • Helo, S.;Manger, J. P.;Krupski, T. L.

  Prostate cancer is known to have a tissue tropism for bone. This tissue tropism coupled with the experience with androgen deprivation therapy (ADT) over the past decade has led to heightened awareness of bone complications. Osteopenia and subsequent skeletal-related events (SREs) are one of the more concerning repercussions of ADT along with cardiovascular sequelae. To combat this decrease in bone mineral density, several agents have been developed for bone protection. The largest experience is with bisphosphonates (BPs), but recently (2011) head to head trials have established the role of monoclonal antibodies, particularly in patients with prostate cancer bone metastasis. For patients initiating ADT, monthly denosumab increased bone mineral density, the time for occurrence of any bone metastasis and time for symptomatic bone metastasis. Denosumab is a fully human monoclonal antibody of the IgG2 subtype that selectively binds and neutralizes receptor activator NF kappa B ligand ...

  
  

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

Mené sur 924 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase III évalue, du point de vue de la survie globale, le vandetanib après l'échec d'un traitement par inhibiteur d'EGFR et d'un ou deux protocoles de chimiothérapie

• Vandetanib Versus Placebo in Patients With Advanced Non–Small-Cell Lung Cancer After Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR)
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 924 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase III évalue, du point de vue de la survie globale, le vandetanib après l'échec d'un traitement par inhibiteur d'EGFR et d'un ou deux protocoles de chimiothérapie

  “Vandetanib Versus Placebo in Patients With Advanced Non–Small-Cell Lung Cancer After Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR)”

  • Lee, Jin Soo;Hirsh, Vera;Park, Keunchil;Qin, Shukui;Blajman, Cesar R.;Perng, Reury-Perng;Chen, Yuh-Min;Emerson, Laura;Langmuir, Peter;Manegold, Christian

  Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor (EGFR), and RET signaling. This placebo-controlled trial assessed whether vandetanib conferred an overall survival benefit in patients with advanced non–small-cell lung cancer (NSCLC) after prior treatment with an EGFR tyrosine kinase inhibitor and one or two chemotherapy regimens.Patients and Methods Eligible patients were randomly assigned 2:1 to receive vandetanib 300 mg/d or placebo until disease progression or unacceptable toxicity. The primary objective was to compare the outcomes between the two arms with respect to overall survival.Results Overall, 924 patients received vandetanib (n = 617) or placebo (n = 307). No significant increase in overall survival was detected in the vandetanib cohort compared with placebo (hazard ratio = 0.95; 95.2% CI, 0.81 to 1.11; P = .527); median overall survival was 8.5 months versus 7.8 months for vandetanib and ...

  
  

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

Cet article passe en revue les avantages et les limites du vemurafenib et de l'ipilimumab pour le traitement d'un mélanome métastatique, puis identifie des essais cliniques susceptibles de surmonter les limites actuelles de ces traitements

• Therapy for metastatic melanoma: the past, present, and future
  • BMC Medicine, Vol. 10 (1), pp. 23, 2012 (article en libre accès)
  Détails

  Fermer

  Cet article passe en revue les avantages et les limites du vemurafenib et de l'ipilimumab pour le traitement d'un mélanome métastatique, puis identifie des essais cliniques susceptibles de surmonter les limites actuelles de ces traitements

  “Therapy for metastatic melanoma: the past, present, and future”

  • Finn, Laura;Markovic, Svetomir;Joseph, Richard

  Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the FDA approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians, and while these therapies have their limitations; they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise.

  
  

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

Menés respectivement sur 219 et 309 patients, ces deux essais évaluent le ruxolitinib, un inhibiteur sélectif de JAK, dans le traitement d'une myélofibrose

• A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis
  • New England Journal of Medicine, Vol. 366 (9), pp. 799-807, 2012 (résumé)
  Détails

  Fermer

  Menés respectivement sur 219 et 309 patients, ces deux essais évaluent le ruxolitinib, un inhibiteur sélectif de JAK, dans le traitement d'une myélofibrose

  “A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis”

  • Verstovsek, Srdan;Mesa, Ruben A.;Gotlib, Jason;Levy, Richard S.;Gupta, Vikas;DiPersio, John F.;Catalano, John V.;Deininger, Michael;Miller, Carole;Silver, Richard T.;Talpaz, Moshe;Winton, Elliott F.;Harvey, Jimmie H.;Arcasoy, Murat O.;Hexner, Elizabeth;Lyons, Roger M.;Paquette, Ronald;Raza, Azra;Vaddi, Kris;Erickson-Viitanen, Susan;Koumenis, Iphigenia L.;Sun, William;Sandor, Victor;Kantarjian, Hagop M.

  Background: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. Methods: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. Results: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score ...

  
  
• JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis
  • New England Journal of Medicine, Vol. 366 (9), pp. 787-798, 2012 (résumé)
  Détails

  Fermer

  Menés respectivement sur 219 et 309 patients, ces deux essais évaluent le ruxolitinib, un inhibiteur sélectif de JAK, dans le traitement d'une myélofibrose

  “JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis”

  • Harrison, Claire ; Kiladjian, Jean-Jacques ; Al-Ali, Haifa Kathrin ; Gisslinger, Heinz ; Waltzman, Roger ; Stalbovskaya, Viktoriya ; McQuitty, Mari ; Hunter, Deborah S. ; Levy, Richard ; Knoops, Laurent ; Cervantes, Francisco ; Vannucchi, Alessandro M. ; Barbui, Tiziano ; Barosi, Giovanni

  Background: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. Methods: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. Results: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 ...

  
  
• Challenges Facing JAK Inhibitor Therapy for Myeloproliferative Neoplasms
  • New England Journal of Medicine, Vol. 366 (9), pp. 844-846, 2012 (éditorial)
  Détails

  Fermer

  Menés respectivement sur 219 et 309 patients, ces deux essais évaluent le ruxolitinib, un inhibiteur sélectif de JAK, dans le traitement d'une myélofibrose

  “Challenges Facing JAK Inhibitor Therapy for Myeloproliferative Neoplasms”

  • Tefferi, Ayalew

  William Vainchenker discovered the gain-of-function mutation in the gene encoding Janus kinase (JAK) 2 (JAK2 V617F) in early 2004 (reported in 2005)1 and subsequently described its association with BCR-ABL1–negative myeloproliferative neoplasms and its ability to induce erythrocytosis in mice. At that time, many researchers hoped that a specific targeted agent would be developed for these neoplasms, similar to imatinib for chronic myeloid leukemia. This particular prospect was bolstered by the detection of other activating mutations that are relevant to JAK–signal transducer and activator of transcription (STAT) (e.g., MPL W515L and JAK2 K539L) in patients with JAK2 V617F–negative disease. . . .

  
  

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

Menée sur 60 patients pédiatriques atteints d'un rétiblastome, cette étude évalue les effets ototoxiques associés à un traitement au carboplatine

• Carboplatin-Associated Ototoxicity in Children With Retinoblastoma
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur 60 patients pédiatriques atteints d'un rétiblastome, cette étude évalue les effets ototoxiques associés à un traitement au carboplatine

  “Carboplatin-Associated Ototoxicity in Children With Retinoblastoma”

  • Qaddoumi, Ibrahim;Bass, Johnnie K.;Wu, Jianrong;Billups, Catherine A.;Wozniak, Amy W.;Merchant, Thomas E.;Haik, Barrett G.;Wilson, Matthew W.;Rodriguez-Galindo, Carlos

  Purpose Carboplatin-induced ototoxicity remains poorly defined but is of potential great consequence in children with retinoblastoma. We retrospectively assessed the incidence of ototoxicity and its risk factors in children with retinoblastoma who were treated with carboplatin.Patients and Methods We reviewed the audiologic test results of 60 patients with retinoblastoma who received front-line treatment with systemic carboplatin and vincristine according to the St Jude RET-3 protocol (n = 23) or best clinical management (n = 37). Ototoxicity was evaluated by three different grading systems.Results Twelve patients (20%) developed ototoxicity at some time after treatment initiation; however, ototoxicity resolved in two patients, and thus,10 patients (17%) had sustained hearing loss as documented at their most recent audiologic evaluation. Nine of these 10 patients had grade 3 or 4 ototoxicity, and nine patients were less than 6 months of age at the start of chemotherapy. Age at the ...

  
  
• A Cautionary Tale: Dosing Chemotherapy in Infants With Retinoblastoma
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
  Détails

  Fermer

  Menée sur 60 patients pédiatriques atteints d'un rétinoblastome, cette étude évalue les effets ototoxiques associés à un traitement au carboplatine

  “A Cautionary Tale: Dosing Chemotherapy in Infants With Retinoblastoma”

  • Leahey, Ann

  
  

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

Mené sur 626 patients atteints d'un cancer urothélial métastatique ou localement avancé, cet essai de phase III évalue, du point de vue de la survie globale (durée médiane de suivi : 6,6 ans), l'ajout de paclitaxel à une combinaison gemcitabine plus cisplatine

• Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Mené sur 626 patients atteints d'un cancer urothélial métastatique ou localement avancé, cet essai de phase III évalue, du point de vue de la survie globale (durée médiane de suivi : 6,6 ans), l'ajout de paclitaxel à une combinaison gemcitabine plus cisplatine

  “Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987”

  • Bellmunt, Joaquim;von der Maase, Hans;Mead, Graham M.;Skoneczna, Iwona;De Santis, Maria;Daugaard, Gedske;Boehle, Andreas;Chevreau, Christine;Paz-Ares, Luis;Laufman, Leslie R.;Winquist, Eric;Raghavan, Derek;Marreaud, Sandrine;Collette, Sandra;Sylvester, Richard;de Wit, Ronald

  Purpose The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival.Patients and Methods We conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity.Results From 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio [HR], 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as ...

  
  

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

Menée sur 224 patients atteints d'un cancer colorectal inopérable et présentant des métastases hépatiques, cette étude évalue l'efficacité d'un protocole de chimio-embolisation répétée combinant ou non plusieurs agents chimiothérapiques en vue d'une thermothérapie interstitielle par laser guidé par IRM

• Repeated transarterial chemoembolisation using different chemotherapeutic drug combinations followed by MR-guided laser-induced thermotherapy in patients with liver metastases of colorectal carcinoma
  • British Journal of Cancer, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur 224 patients atteints d'un cancer colorectal inopérable et présentant des métastases hépatiques, cette étude évalue l'efficacité d'un protocole de chimio-embolisation répétée combinant ou non plusieurs agents chimiothérapiques en vue d'une thermothérapie interstitielle par laser guidé par IRM

  “Repeated transarterial chemoembolisation using different chemotherapeutic drug combinations followed by MR-guided laser-induced thermotherapy in patients with liver metastases of colorectal carcinoma”

  • Vogl, T. J.;Jost, A.;Nour-Eldin, N. A.;Mack, M. G.;Zangos, S.;Naguib, N. N. N.

  Background : To evaluate a treatment protocol with repeated transarterial-chemoembolisation (TACE) downsizing before MR-guided laser-induced interstitial thermotherapy (LITT) using different chemotherapeutic combinations in patients with unresectable colorectal cancer (CRC) liver metastases. Methods : Two hundred and twenty-four patients were included in the current study. Transarterial-chemoembolisation (mean 3.4 sessions per patient) was performed as a downsizing treatment to meet the LITT requirements (numberless than or equal to5, diameter <5 cm). The intra-arterial protocol consisted of either Irinotecan and Mitomycin (n=77), Gemcitabine and Mitomycin (n=49) or Mitomycin alone (n=98) in addition to Lipiodol and Embocept in all patients. Post TACE, all patients underwent LITT (mean 2.2 sessions per patient). Results : Overall, TACE resulted in a mean reduction in diameter of the target lesions of 21.4%. The median time to progression was 8 months, calculated from the start of ...

  
  

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

A partir de données portant sur 1 181 patients ayant été inclus dans un essai de phase I d'une thérapie ciblée, cette étude évalue le taux de toxicité sévère associée aux traitements

• Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience
  • Annals of Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  A partir de données portant sur 1 181 patients ayant été inclus dans un essai de phase I d'une thérapie ciblée, cette étude évalue le taux de toxicité sévère associée aux traitements

  “Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience”

  • Wheler, J. J.;Tsimberidou, A. M.;Hong, D. S.;Naing, A.;Falchook, G. S.;Fu, S.;Moulder, S.;Stephen, B.;Wen, S.;Kurzrock, R.

  Background: This study assessed toxicity in advanced cancer patients treated in a phase I clinic that focuses on targeted agents.Patients and methods: An analysis of database records of 1181 consecutive patients with advanced cancer who were treated in the phase I program starting 1 January 2006 was carried out.Results: All patients were treated on at least 1 of the 82 phase I clinical trials. Overall, 56 trials (68.3%) had only targeted agents, 13 (15.9%) only cytotoxics, and 13 (15.9%) targeted and cytotoxic agents. Rates of grade 3 and 4 toxicity that were at least possibly drug related were 7.1% and 3.2%, respectively, and 5 of the 1181 patients (0.4%) died from toxicity that was at least possibly drug related. The most common grade 3 or more toxic effects were neutropenia, thrombocytopenia, anemia, dehydration, infection, altered mental status, bleeding, vomiting, nausea, and diarrhea. Eastern Cooperative Oncology Group (ECOG) performance status greater than zero and use of a ...

  
  

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

Cette étude analyse les raisons de la baisse d'efficacité de l'activité Recherche et Développement de l'industrie pharmaceutique sur les dernières décennies

• Diagnosing the decline in pharmaceutical R&D efficiency
  • Nature Reviews Drug Discovery, Vol. 11 (3), pp. 191-200, 2012 (résumé)
  Détails

  Fermer

  Cette étude analyse les raisons de la baisse d'efficacité de l'activité Recherche et Développement de l'industrie pharmaceutique sur les dernières décennies

  “Diagnosing the decline in pharmaceutical R&D efficiency”

  • Scannell, Jack W.;Blanckley, Alex;Boldon, Helen;Warrington, Brian

  The past 60 years have seen huge advances in many of the scientific, technological and managerial factors that should tend to raise the efficiency of commercial drug research and development (R&D). Yet the number of new drugs approved per billion US dollars spent on R&D has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solutions to the problem of declining R&D efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the number of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the 'better than the Beatles' problem; the 'cautious regulator' problem; the 'throw money at it' tendency; and the 'basic research–brute force' bias. Our aim is to provoke a more systematic analysis of the causes of the decline in ...

  
  

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

Cet article passe en revue les nouvelles approches précliniques et cliniques susceptibles d'accélérer le processus d'autorisation de mise sur le marché des médicaments anticancéreux

• Drug development and clinical trials-the path to an approved cancer drug
  • Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les nouvelles approches précliniques et cliniques susceptibles d'accélérer le processus d'autorisation de mise sur le marché des médicaments anticancéreux

  “Drug development and clinical trials-the path to an approved cancer drug”

  • Rubin, Eric H.;Gilliland, D. Gary

  Advances in our understanding of cancer biology have led to the discovery of a spectrum of new therapeutic targets. However, despite remarkable progress in the identification and characterization of novel mechanisms of the oncogenic process, the success rate for approval of oncology drugs remains low relative to other therapeutic areas. Innovative preclinical and clinical approaches, such as the use of advanced genomic technologies, as well as branched adaptive clinical trial designs, have the potential to accelerate the development and approval of highly effective oncology drugs, along with a matching diagnostic test to identify those patients most likely to benefit from the new treatment. To maximize the effectiveness of these new strategies, close collaboration between academic, industry, and regulatory agencies will be required. In this Review, we highlight new approaches in preclinical and clinical drug development that will help accelerate approval of drugs, and aim to provide ...

  
  

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

Cet article analyse la pertinence du critère de survie sans progression dans les essais cliniques de traitements anticancéreux

• Progression-Free Survival: Meaningful or Simply Measurable?
  • Journal of Clinical Oncology, sous presse, 2012 (commentaire)
  Détails

  Fermer

  Cet article analyse la pertinence du critère de survie sans progression dans les essais cliniques de traitements anticancéreux

  “Progression-Free Survival: Meaningful or Simply Measurable?”

  • Booth, Christopher M.;Eisenhauer, Elizabeth A.

  
  

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