Traitements

Menée sur 52 patients atteints d'un cancer des voies biliaires extra-hépatiques et ayant subi une intervention chirurgicale entre 2000 et 2010, cette étude monocentrique évalue, du point de vue de la survie globale, du contrôle locorégional de la maladie et de la présence de métastases distantes, l'efficacité d'une radiothérapie adjuvante pour traiter des micro- tumeurs résiduelles

• Impact of Adjuvant Radiation Therapy for Microscopic Residual Tumor After Resection of Extrahepatic Bile Duct Cancer
  • American Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Menée sur 52 patients atteints d'un cancer des voies biliaires extra-hépatiques et ayant subi une intervention chirurgicale entre 2000 et 2010, cette étude monocentrique évalue, du point de vue de la survie globale, du contrôle locorégional de la maladie et de la présence de métastases distantes, l'efficacité d'une radiothérapie adjuvante pour traiter des micro- tumeurs résiduelles

  “Impact of Adjuvant Radiation Therapy for Microscopic Residual Tumor After Resection of Extrahepatic Bile Duct Cancer”

  • Matsuda, Takeru;Fujita, Hirofumi;Harada, Naoki;Kunimoto, Yukihiro;Tanaka, Tomohiro;Kimura, Taisei;Kitaoka, Hironori;Asano, Eisuke;Hosono, Masayoshi;Hayashi, Tomomi;Ogino, Kazunori

  Objectives: The effect of adjuvant radiation therapy (RT) in extrahepatic bile duct (EHBD) cancer patients with microscopic-positive resection margins (R1 resection) is still controversial. Methods: Between January 2000 and March 2010, 52 patients with EHBD cancer underwent surgery at our institution, of whom 36 were subjected to a retrospective analysis. Eleven patients received adjuvant RT after resection [surgery (S)+RT group], which included 9 patients with R1 resection and 2 with para-aortic lymph node metastasis. Their oncological outcomes were analyzed and compared with those of the 25 patients with R0 resection who did not receive adjuvant RT (S group). Results: Patients in the S+RT group had significantly more advanced disease than those in the S group. However, there was no significant difference in disease-free survival or overall survival between the 2 groups. Median survival times for the S+RT and the S groups were 44 and 47 months, respectively, whereas the 5-year ...

  
  

Mots clés : Voies biliaires; Traitements (Traitements localisés : applications cliniques)

Menée sur 196 patients atteints d'un cancer de la vessie traité entre 2003 et 2011, cette étude évalue la fréquence, la nature et la gravité des complications post-opératoires associées à une cystectomie radicale assistée par robot

• Standardized Analysis of Frequency and Severity of Complications After Robot-assisted Radical Cystectomy
  • European urology, sous presse, 2012 (résumé)
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  Menée sur 196 patients atteints d'un cancer de la vessie traité entre 2003 et 2011, cette étude évalue la fréquence, la nature et la gravité des complications post-opératoires associées à une cystectomie radicale assistée par robot

  “Standardized Analysis of Frequency and Severity of Complications After Robot-assisted Radical Cystectomy”

  • Bertram, E. Yuh;Michael, Nazmy;Nora, H. Ruel;Jason, T. Jankowski;Anita, R. Menchaca;Robert, R. Torrey;Jennifer, A. Linehan;Clayton, S. Lau;Kevin, G. Chan;Timothy, G. Wilson

  Background : Comprehensive and standardized reporting of adverse events after robot-assisted radical cystectomy (RARC) and urinary diversion for bladder cancer is necessary to evaluate the magnitude of morbidity for this complex operation. Objective : To accurately identify and assess postoperative morbidity after RARC using a standardized reporting system. Design, setting, and participants : A total of 241 consecutive patients underwent RARC, extended pelvic lymph node dissection, and urinary diversion between 2003 and 2011. In all, 196 patients consented to a prospective database, and they are the subject of this report. Continent diversions were performed in 68% of cases. Outcome measurements and statistical analysis : All complications within 90 d of surgery were defined and categorized by a five-grade and 10-domain modification of the Clavien system. Univariable and multivariable logistic regression analyses were used to identify predictors of complications. Grade 1–2 ...

  
  

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

Menée sur 103 patients atteints d'un cancer, cette étude rétrospective évalue, du point de vue de la survie globale et de la survie sans récidive intra-crânienne, l'intérêt d'une radiochirurgie stéréotaxique par Gamma Knife pour traiter 5 métastases cérébrales ou plus

• Survival and Intracranial Control of Patients With 5 or More Brain Metastases Treated With Gamma Knife Stereotactic Radiosurgery
  • American Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Menée sur 103 patients atteints d'un cancer, cette étude rétrospective évalue, du point de vue de la survie globale et de la survie sans récidive intra-crânienne, l'intérêt d'une radiochirurgie stéréotaxique par Gamma Knife pour traiter 5 métastases cérébrales ou plus

  “Survival and Intracranial Control of Patients With 5 or More Brain Metastases Treated With Gamma Knife Stereotactic Radiosurgery”

  • Raldow, Ann C.;Chiang, Veronica L.;Knisely, Jonathan P.;Yu, James B.

  Purpose: Limited data are available to help inform decisions about stereotactic radiosurgery for patients with >=5 brain metastases. We therefore performed a retrospective analysis of patients treated for >5 brain metastases. Materials/Methods: Patients who underwent treatment for >=5 brain metastases from October 2000 to September 2010 were identified. Overall survival (OS) for each patient was calculated from the date of first treatment of >=5 metastases. Intracranial recurrence-free survival was defined when posttreatment magnetic resonance imaginag showed evidence for disease progression. Cox proportional hazards regression was performed for OS and intracranial recurrence free survival. Variables included sex, age, Karnofsky Performance Status (KPS), histology, prior whole-brain radiation treatment or Gamma Knife treatment, and number of metastases treated. Results: A total of 103 patients were identified. Median OS was 8.3 months. Median OS was 7.6 months and 8.3 months, for ...

  
  

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

Menée sur 69 patientes atteintes d'un carcinome canalaire invasif ou in situ de stade précoce et traitées par tumorectomie (âge : 50 ans ou plus), cette étude multicentrique évalue, du point de vue du taux de récidive, de la nature et de la gravité des événements indésirables, les résultats cliniques associés à une brachythérapie électronique ainsi que la qualité de vie des patientes un an après l'opération

• Postsurgical Treatment of Early-stage Breast Cancer With Electronic Brachytherapy: Outcomes and Health-related Quality of Life at 1 Year
  • American Journal of Clinical Oncology, sous presse, 2012 (article en libre accès)
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  Menée sur 69 patientes atteintes d'un carcinome canalaire invasif ou in situ de stade précoce et traitées par tumorectomie (âge : 50 ans ou plus), cette étude multicentrique évalue, du point de vue du taux de récidive, de la nature et de la gravité des événements indésirables, les résultats cliniques associés à une brachythérapie électronique ainsi que la qualité de vie des patientes un an après l'opération

  “Postsurgical Treatment of Early-stage Breast Cancer With Electronic Brachytherapy: Outcomes and Health-related Quality of Life at 1 Year”

  • Patel, Rakesh R.;Beitsch, Peter D.;Nichols, Timothy D.;Lorenzetti, John D.;Wurzer, James C.;Tucker, James C.;Nunn, George W.;Laduzinsky, Susan J.;Kugler, Morris A.;Simmons, Dwelvin L.;Gilligan, Michael S.;Roy, Tapan;Foley, Jonathon K.;Thropay, John P.;Odou, Mark William;Bornstein, Bruce A.;Tito, Elizabeth P.;Chadha, Manjeet;Boolbol, Susan K.;Lane, Steven C.;White, Julie G.

  Objectives: This multicenter registry followed up patients with early-stage breast cancer treated with breast-conserving surgery and electronic brachytherapy (EBT). This report provides 1- and 2-year updates to the initial publication. Methods: Patients were of age 50 years or more with invasive carcinoma or ductal carcinoma in situ, tumor size <=3 cm, and negative surgical margins. After lumpectomy, patients received EBT in 10 fractions over 5 days (34 Gy total). Results: Of the 69 patients enrolled, 62 were evaluated at 1 year and 20 patients at 2 years after treatment. At 1 year, 28 (45.2%) patients reported adverse events that were possibly, probably, or definitely related to treatment. Most (90%) were grade 1: manageable and typical of radiation therapy. Four events were grade 2: induration/firmness (2), field contracture (1), and seroma (1). One event was grade 3: a draining fistula at the lumpectomy site due to residual effects of a breast infection at 1 month. No recurrences ...

  
  

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

Cet article passe en revue les avancées concernant les techniques d'imagerie et analyse leur rôle dans le traitement des patients atteints d'un cancer de la prostate avec métastases ganglionnaires

• Management of prostate cancer patients with lymph node involvement: A rapidly evolving paradigm
  • Cancer treatment reviews, sous presse, 2012 (résumé)
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  Cet article passe en revue les avancées concernant les techniques d'imagerie et analyse leur rôle dans le traitement des patients atteints d'un cancer de la prostate avec métastases ganglionnaires

  “Management of prostate cancer patients with lymph node involvement: A rapidly evolving paradigm”

  • Créhange, Gilles;Chen, Chien Peter;Hsu, Charles C.;Kased, Norbert;Coakley, Fergus V.;Kurhanewicz, John;Roach, Mack

  Although widespread PSA screening has inevitably led to increased diagnosis of lower risk prostate cancer, the number of patients with nodal involvement at baseline remains high (nearly 40% of high risk patients initially staged cN0). These rates probably do not reflect the true incidence of prostate cancer with lymph node involvement among patients selected for external beam radiotherapy (EBRT), as patients selected for surgery often have more favorable prognostic features. At many institutions, radical treatment directed only at the prostate is considered standard and patients known to have regional disease are often managed palliatively with androgen deprivation therapy (ADT) for presumed systemic disease. New imaging tools such as MR lymphangiography, choline-based PET imaging or combined SPECT/CT now allow surgeons and radiation oncologists to identify and target nodal metastasis and/or lymph nodes with a high risk of occult involvement. Recent advances in the field of surgery ...

  
  

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

Cet article passe en revue les études récentes concernant l'utilisation de la chirurgie assistée par robot pour traiter des cancers gynécologiques, puis analyse ses avantages et ses inconvénients

• Robotic surgery in gynecologic oncology
  • Current Opinion in Oncology, sous presse, 2012 (résumé)
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  Cet article passe en revue les études récentes concernant l'utilisation de la chirurgie assistée par robot pour traiter des cancers gynécologiques, puis analyse ses avantages et ses inconvénients

  “Robotic surgery in gynecologic oncology”

  • Fleming, Nicole D.;Ramirez, Pedro T.

  Purpose of review: The objective of this article is to review the recently published literature on the use of robotic surgery in the management of gynecologic malignancies. Recent findings: Retrospective data collected from many institutions support the use of robotic surgery in the management of cervical, endometrial, and early-stage ovarian cancer. Benefits to robotic surgery include decreased blood loss, fewer perioperative complications, and decreased length of hospital stay, especially when compared to an open cohort. Disadvantages include costs associated with the robotic system and disposable equipment, accessibility to robotic surgical systems, loss of haptic sensation with the device, and lack of prospective trials validating its use in gynecologic oncology. Summary : Current evidence establishes a role for the use of robotic surgery in the treatment of gynecologic malignancies. Further research should be implemented to validate the use of robotic surgery in gynecologic ...

  
  

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

Menée à l'aide de xénogreffes de cancer ovarien, cette étude évalue l'activité antitumorale d'un traitement combinant le bévacizumab et le cixutumumab, un anticorps bloquant la signalisation IGF-1

• Targeting the Insulin Growth Factor and the Vascular Endothelial Growth Factor Pathways in Ovarian Cancer
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée à l'aide de xénogreffes de cancer ovarien, cette étude évalue l'activité antitumorale d'un traitement combinant le bévacizumab et le cixutumumab, un anticorps bloquant la signalisation IGF-1

  “Targeting the Insulin Growth Factor and the Vascular Endothelial Growth Factor Pathways in Ovarian Cancer”

  • Shao, Minghai;Hollar, Stacy;Chambliss, Daphne;Schmitt, Jordan;Emerson, Robert;Chelladurai, Bhadrani;Perkins, Susan;Ivan, Mircea;Matei, Daniela

  Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl ...

  
  

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

Menée à l'aide de modèles murins de mélanome, cette étude suggère que le vémurafenib, un inhibiteur de l'oncogène BRAFV600E, renforce l'efficacité d'une immunothérapie par transfert adoptif de cellules

• BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée à l'aide de modèles murins de mélanome, cette étude suggère que le vémurafenib, un inhibiteur de l'oncogène BRAFV600E, renforce l'efficacité d'une immunothérapie par transfert adoptif de cellules

  “BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy”

  • Koya, Richard C.;Mok, Stephen;Otte, Nicholas;Blacketor, Kevin J;Comin-Anduix, Begona;Tumeh, Paul C;Minasyan, Aspram;Graham, Nicholas;Graeber, Thomas G;Chodon, Thinle;Ribas, Antoni

  Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. Here, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer (ACT) therapy with lymphocytes genetically modified with a T cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors, or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1, resulted in superior antitumor responses compared with either therapy alone. T cell analysis demonstrated that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased MAPK ...

  
  

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

Menée in vitro et à l'aide de xénogreffes, cette étude suggère que la combinaison du lénalidomide et de l'ibrutinib, un inhibiteur de BTK, mettrait en oeuvre un mécanisme de létalité synthétique efficace pour le traitement du sous-type ABC des lymphomes diffus à grandes cellules B

• Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma
  • Cancer cell, Vol. 21 (6), pp. 723-737, 2012 (résumé)
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  Menée in vitro et à l'aide de xénogreffes, cette étude suggère que la combinaison du lénalidomide et de l'ibrutinib, un inhibiteur de BTK, mettrait en oeuvre un mécanisme de létalité synthétique efficace pour le traitement du sous-type ABC des lymphomes diffus à grandes cellules B

  “Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma”

  • Yang, Yibin;Shaffer, Arthur L;Emre, N. C.  Tolga;Ceribelli, Michele;Zhang, Meili;Wright, George;Xiao, Wenming;Powell, John;Platig, John;Kohlhammer, Holger;Young, Ryan M;Zhao, Hong;Yang, Yandan;Xu, Weihong;Buggy, Joseph J;Balasubramanian, Sriram;Mathews, Lesley A;Shinn, Paul;Guha, Rajarshi;Ferrer, Marc;Thomas, Craig;Waldmann, Thomas A;Staudt, Louis M

  Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon ² (IFN²) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFN² production by repressing IRF7 and amplify prosurvival NF-ºB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies. º Lenalidomide kills ABC DLBCLs by decreasing expression of IRF4 and SPIB º IRF4 and SPIB maintain ABC DLBCL ...

  
  

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

Menée sur 10 patients atteints d'un cancer colorectal avec métastases hépatiques, cette étude évalue la faisabilité d'une injection intraveineuse d'un réovirus oncolytique, avant l'opération chirurgicale, et la présence de ce virus dans les métastases excisées

• Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients
  • Science Translational Medicine, Vol. 4 (138), pp. 138ra77, 2012 (résumé)
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  Menée sur 10 patients atteints d'un cancer colorectal avec métastases hépatiques, cette étude évalue la faisabilité d'une injection intraveineuse d'un réovirus oncolytique, avant l'opération chirurgicale, et la présence de ce virus dans les métastases excisées

  “Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients”

  • Adair, Robert A.;Roulstone, Victoria;Scott, Karen J.;Morgan, Ruth;Nuovo, Gerard J.;Fuller, Martin;Beirne, Deborah;West, Emma J.;Jennings, Victoria A.;Rose, Ailsa;Kyula, Joan;Fraser, Sheila;Dave, Rajiv;Anthoney, David A.;Merrick, Alison;Prestwich, Robin;Aldouri, Amer;Donnelly, Oliver;Pandha, Hardev;Coffey, Matt;Selby, Peter;Vile, Richard;Toogood, Giles;Harrington, Kevin;Melcher, Alan A.

  Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential ...

  
  
• The Virus That Came In from the Cold
  • Science Translational Medicine, Vol. 4 (138), pp. 138fs17, 2012 (commentaire)
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  Mené sur 10 patients atteints d'un cancer colorectal avec métastases hépatiques, cette étude évalue la faisabilité d'une injection intraveineuse d'un réovirus oncolytique, avant l'opération chirurgicale, et la présence de ce virus dans les métastases excisées

  “The Virus That Came In from the Cold”

  • Bell, John C.

  A common-cold virus uses an undercover strategy to avoid neutralizing antibodies in cancer patients and targets distant sites of metastatic cancer growth.

  
  

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

Menée in vitro et à l'aide de trois modèles murins, cette étude évalue l'activité antitumorale d'une nouvelle immunocytokine, formée par un anticorps et l'interleukine 12, en combinaison avec du paclitaxel

• The antibody-based delivery of interleukin-12 to the tumor neo-vasculature eradicates cancer in combination with paclitaxel
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Menée in vitro et à l'aide de trois modèles murins, cette étude évalue l'activité antitumorale d'une nouvelle immunocytokine, formée par un anticorps et l'interleukine 12, en combinaison avec du paclitaxel

  “The antibody-based delivery of interleukin-12 to the tumor neo-vasculature eradicates cancer in combination with paclitaxel”

  • Pasche, Nadine;Wulhfard, Sarah;Pretto, Francesca;Carugati, Elisa;Neri, Dario

  Purpose:Interleukin-12 (IL12) is a potent proinflammatory cytokine with antitumor activity. Its heterodimeric nature makes it compatible with a large variety of different immunocytokine formats. Here we report the design, production and characterization of a novel immunocytokine, based on the fusion of the F8 antibody (specific to the alternatively spliced EDA domain of fibronectin, a marker of tumor neo-vasculature) with IL12 (termed IL12-F8-F8). Experimental Design:We developed a novel immunocytokine based on the sequential fusion of interleukin-12 as a single polypeptide with two F8 antibodies in single-chain Fv (scFv) format. The fusion protein was characterized in vitro and its targeting performance was assessed in vivo. The immunocytokine antitumor activity was studied as monotherapy as well as in combination therapies in three different murine tumor models. Moreover, depletion experiments and tumor analysis revealed a dominant role of NK cells for the mechanism of action ...

  
  

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

Menée in vitro et in vivo, cette étude évalue les effets d'un composé appelé WZB117, qui inhibe le transport de glucose, sur la croissance de cellules tumorales

• A small molecule inhibitor of glucose transporter 1 down-regulates glycolysis, induces cell cycle arrest, and inhibits cancer cell growth in vitro and in vivo
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude évalue les effets d'un composé appelé WZB117, qui inhibe le transport de glucose, sur la croissance de cellules tumorales

  “A small molecule inhibitor of glucose transporter 1 down-regulates glycolysis, induces cell cycle arrest, and inhibits cancer cell growth in vitro and in vivo”

  • Liu, Yi;Cao, Yanyan;Zhang, Weihe;Bergmeier, Stephen;Qian, Yanrong;Akbar, Huzoor;Colvin, Robert;Ding, Juan;Tong, Lingying;Wu, Shiyong;Hines, Jennifer;Chen, Xiaozhuo

  The functional and therapeutic importance of the Warburg effect is increasingly recognized and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal (ip) injection of WZB117 at 10 mg/kg resulted in an over 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, ...

  
  

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

Mené sur 84 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé PX-866, un inhibiteur de PI3K

• A Multicenter Phase 1 Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Mené sur 84 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé PX-866, un inhibiteur de PI3K

  “A Multicenter Phase 1 Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors”

  • Hong, David S.;Bowles, Daniel W;Falchook, Gerald S.;Messersmith, Wells A.;George, Goldy C.;O'Bryant, Cindy L.;Vo, Alex CH;Klucher, Kevin;Herbst, Roy S.;Eckhardt, S. Gail;Peterson, Scott;Hausman, Diana F;Kuzrock, Razelle;Jimeno, Antonio

  Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics (PK), and antitumor activity of PX-866 in patients with incurable cancers. Patients and Methods: This was a phase 1, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (Arm 1; days 1-5 and 8-12 of a 28-day cycle) or continuous (Arm 2; days 1-28 of a 28-day cycle) schedule. Additional patients were treated at the Arm 2 MTD in a food effects sub-study. Results: Eighty-four patients were treated in the Arm 1 (n=51), Arm 2 (n=20) and food effects (n = 13) cohorts. The most frequent study drug-related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12mg and 8mg for Arm 1 and 2, respectively. The dose-limiting toxicities (DLTs) consisted of grade 3 (g3) diarrhea (n=3) and g3 elevated AST (n=1). The PK profile was dose proportional, with no ...

  
  

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

Menée in vitro, cette étude suggère que les petites molécules inhibant l'activité tyrosine kinase des gènes de la famille JAK ont également des effets de nature immunologique

• Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells
  • The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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  Menée in vitro, cette étude suggère que les petites molécules inhibant l'activité tyrosine kinase des gènes de la famille JAK ont également des effets de nature immunologique

  “Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells”

  • Bellucci, Roberto;Nguyen, Hong-Nam;Martin, Allison;Heinrichs, Stefan;Schinzel, Anna C.;Hahn, William C.;Ritz, Jerome

  Natural killer (NK) cells are primary effectors of innate immunity directed against transformed tumor cells. In response, tumor cells have developed mechanisms to evade NK cell–mediated lysis through molecular mechanisms that are not well understood. In the present study, we used a lentiviral shRNA library targeting more than 1,000 human genes to identify 83 genes that promote target cell resistance to human NK cell–mediated killing. Many of the genes identified in this genetic screen belong to common signaling pathways; however, none of them have previously been known to modulate susceptibility of human tumor cells to immunologic destruction. Gene silencing of two members of the JAK family (JAK1 and JAK2) increased the susceptibility of a variety of tumor cell types to NK-mediated lysis and induced increased secretion of IFN-γ by NK cells. Treatment of tumor cells with JAK inhibitors also increased susceptibility to NK cell activity. These findings may have important clinical ...

  
  

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

Mené sur 3 323 patientes atteintes d'un cancer du sein de stade 1-3, cet essai multicentrique randomisé évalue, du point de vue de la survie sans maladie, l'efficacité d'un bisphosphonate par voie orale, le clodronate (durée médiane de suivi: 90,7 mois)

• Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené sur 3 323 patientes atteintes d'un cancer du sein de stade 1-3, cet essai multicentrique randomisé évalue, du point de vue de la survie sans maladie, l'efficacité d'un bisphosphonate par voie orale, le clodronate (durée médiane de suivi: 90,7 mois)

  “Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial”

  • Paterson, Alexander H. G.;Anderson, Stewart J.;Lembersky, Barry C.;Fehrenbacher, Louis;Falkson, Carla I.;King, Karen M.;Weir, Lorna M.;Brufsky, Adam M.;Dakhil, Shaker;Lad, Thomas;Baez-Diaz, Luis;Gralow, Julie R.;Robidoux, André;Perez, Edith A.;Zheng, Ping;Geyer, Charles E.;Swain, Sandra M.;Costantino, Joseph P.;Mamounas, Eleftherios P.;Wolmark, Norman

  Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer. NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered withClinicalTrials.gov, numberNCT00009945. Median follow-up was 90·7 months (IQR 82·7?100·0) and 3311 patients had data for this ...

  
  
• Bisphosphonates in early breast cancer
  • The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
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  Mené sur 3 323 patientes atteintes d'un cancer du sein de stade 1-3, cet essai multicentrique randomisé évalue, du point de vue de la survie sans maladie, l'efficacité d'un bisphosphonate par voie orale, le clodronate (durée médiane de suivi: 90,7 mois)

  “Bisphosphonates in early breast cancer”

  • Dubsky, Peter ; Bartsch, Rupert

  In breast cancer treatment, our main focus has remained steadfast on structural, molecular, or functional features of the tumour itself. Clinical and experimental evidence, however, indicates that the complex cycle of tumour formation, growth, and dissemination is an interaction between the cancer cell and the diseased host. In The Lancet Oncology, Alexander Paterson and colleagues report final results of the National Surgical Adjuvant Breast and Bowel Project's protocol B-34 study. In this phase 3 randomised clinical trial undertaken in women with early breast cancer, the investigators targeted the bone microenvironment rather than the tumour with the oral bisphosphonate clodronate.

  
  

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

Cet article décrit l'état de l'art en matière de traitement des lymphomes hodgkiniens

• State of the art in the treatment of Hodgkin lymphoma
  • Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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  Cet article décrit l'état de l'art en matière de traitement des lymphomes hodgkiniens

  “State of the art in the treatment of Hodgkin lymphoma”

  • Borchmann, Peter;Eichenauer, Dennis A.;Engert, Andreas

  Hodgkin lymphoma (HL) has become one of the most easily curable malignancies in oncology. More than 80% of patients can be cured with risk-adapted treatment that includes chemotherapy and radiotherapy. This progress is mainly due to the development of multi-agent chemotherapy and improved radiation techniques; however, severe, life-threatening treatment-related side effects occur, which include organ toxicity and secondary malignancies. Thus, the treatment approaches must be carefully balanced between optimal disease control and the risk of long-term sequelae. Although this article is meant to provide an overview of the current treatment approaches for patients with HL, in many instances conflicting results from various clinical trials are available, and a personal judgment is inevitable. Here, we focus on evidence from large clinical trials with solid conclusions.

  
  

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

Menée sur 240 patients atteints d'un carcinome rhinopharyngé loco-régional de stade avancé, cette étude chinoise compare, du point de vue de la survie globale à 3 ans, de la survie sans maladie ou sans métastases distantes, l'efficacité et la toxicité de trois protocoles de chimioradiothérapie séquentielle à base de cisplatine combinée ou non avec la gemcitabine ou le fluorouracile

• Sequential chemoradiotherapy with gemcitabine and cisplatin for locoregionally advanced nasopharyngeal carcinoma
  • International Journal of Cancer, sous presse, 2012 (résumé)
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  Menée sur 240 patients atteints d'un carcinome rhinopharyngé loco-régional de stade avancé, cette étude chinoise compare, du point de vue de la survie globale à 3 ans, de la survie sans maladie ou sans métastases distantes, l'efficacité et la toxicité de trois protocoles de chimioradiothérapie séquentielle à base de cisplatine combinée ou non avec la gemcitabine ou le fluorouracile

  “Sequential chemoradiotherapy with gemcitabine and cisplatin for locoregionally advanced nasopharyngeal carcinoma”

  • Gu, Mo-Fa;Liu, Li-Zhi;He, Long-Jun;Yuan, Wen-Xin;Zhang, Rong;Luo, Guang-Yu;Xu, Guo-Liang;Zhang, Hua-Man;Yan, Chao-Xian;Li, Jian-Jun

  We investigated a new chemoradiotherapy (CRT) regimen for locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 240 patients were randomly assigned to three different CRT regimens: sequential CRT [1 cycle chemotherapy + Phase I radiotherapy (RT) + 1 cycle chemotherapy + Phase II RT + 2 cycles chemotherapy] with a cisplatin–gemcitabine (GC) regimen (800 mg/m2 gemcitabine on Days 1 and 8 and 20 mg/m2 cisplatin on Days 1–5, every 4 weeks) (sGC-RT); sequential chemoradiotherapy with a cisplatin–fluorouracil (PF) regimen (20 mg/m2 DDP and 500 mg/m2 5-FU on Days 1–5, every 4 weeks) (sPF-RT) and cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy (Con-RT + PF). The complete response rate was higher in the sGC + RT group than in the other two groups (98.75% vs. 92.50%, p < 0.01). The 3-year overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates in the sGC-RT group were significantly higher than those ...

  
  

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

Menée sur 52 patientes atteintes d'un cancer du sein traité par chimiothérapie néoadjuvante puis résection chirurgicale (durée médiane de suivi : 10 ans), cette étude prospective française évalue la toxicité et l'efficacité d'une chimioradiothérapie concomitante adjuvante par rapport à une radiothérapie seule

• Prospective and Comparative Evaluation of the Toxicity of Adjuvant Concurrent Chemoradiotherapy After Neoadjuvant Chemotherapy for Breast Cancer
  • American Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Menée sur 52 patientes atteintes d'un cancer du sein traité par chimiothérapie néoadjuvante puis résection chirurgicale (durée médiane de suivi : 10 ans), cette étude prospective française évalue la toxicité et l'efficacité d'une chimioradiothérapie concomitante adjuvante par rapport à une radiothérapie seule

  “Prospective and Comparative Evaluation of the Toxicity of Adjuvant Concurrent Chemoradiotherapy After Neoadjuvant Chemotherapy for Breast Cancer”

  • Marchand, Virginie;Angelergues, Antoine;Gobaux, Vanessa;Hajage, David;Kirova, Youlia M.;Campana, François;Dendale, Rémi;Reyal, Fabien;Pierga, Jean-Yves;Fourquet, Alain;Bollet, Marc A.

  Purpose: The lack of pathologic breast cancer response to neoadjuvant chemotherapy (NCT), a negative prognostic factor, has prompted the addition of chemotherapy to adjuvant radiotherapy. This study aims to investigate prospectively the toxicities of adjuvant concurrent chemoradiotherapy versus radiotherapy alone. Patients and Methods: Two groups of patients treated for breast cancer between 1997 and 2002 by NCT, surgery, and radiotherapy with or without concurrent chemotherapy, were matched on age, body mass index (BMI), treatment period, treated side, and surgery type. Late toxicity was prospectively evaluated according to the CTCAE v3.0. Acute toxicity was derived from the medical charts. Results: A total of 52 patients were matched. Median follow-up was 10 years. Acute toxicity was higher in the chemoradiotherapy group compared with the radiotherapy alone group: 37% patients versus 10% experienced a grade 2/3 epithelitis (P=0.002); 48% versus 8% experienced a grade >=1 mucositis ...

  
  

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

Menée sur un modèle murin, cette étude évalue la toxicité aiguë d'un traitement combinant un anticorps anti-VEGF et une radiothérapie

• Normal tissues toxicities triggered by combined anti-angiogenic and radiation therapies: hurdles might be ahead
  • British Journal of Cancer, sous presse, 2012 (résumé)
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  Menée sur un modèle murin, cette étude évalue la toxicité aiguë d'un traitement combinant un anticorps anti-VEGF et une radiothérapie

  “Normal tissues toxicities triggered by combined anti-angiogenic and radiation therapies: hurdles might be ahead”

  • Mangoni, M.;Vozenin, M. C.;Biti, G.;Deutsch, E.

  Background : Combined-modality therapy is a promising approach to improve the therapeutic index of radiotherapy. However, these improvements could come at the cost of increased toxicities. Clinical trials evaluating anti-tumour efficacy of bevacizumab combined with radiotherapy have encountered unexpected side effects. This study is the first systematic evaluation of normal tissue toxicity triggered by anti-angiogenic agents combined with radiation therapy in mice. Methods : Effect of a mouse anti-VEGF antibody was monitored on acute toxicity studying radiation-induced intestinal ulceration (12 Gy TBI); on subacute toxicity using a model of oral mucositis (16.5 Gy); on late radiation injuries by monitoring lung fibrosis (bleomycin and 19 Gy). Results : Combination of irradiation with anti-VEGF antibody enhanced intestinal damages with severe epithelial ulcerations, had no adverse impact on oral mucositis and dramatically worsened the fibrotic picture induced by bleomycin and ...

  
  

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

Ces deux articles analysent les enjeux associés aux essais cliniques de type adaptatif pour la recherche de nouveaux traitements

• Adaptive Trials in Clinical Research: Scientific and Ethical Issues to ConsiderAdaptive Trials in Clinical Research
  • JAMA: The Journal of the American Medical Association, Vol. 307 (22), pp. 2379-2380, 2012 (commentaire en libre accès)
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  Ces deux articles analysent les enjeux associés aux essais cliniques de type adaptatif pour la recherche de nouveaux traitements

  “Adaptive Trials in Clinical Research: Scientific and Ethical Issues to ConsiderAdaptive Trials in Clinical Research”

  • van der Graaf, Rieke;Roes, Kit C. B.;van Delden, Johannes J. M.

  Adaptive trials also have certain ethical advantages because fewer participants are assigned to the inferior procedure or drug compared with trials with fixed designs. For instance, in the ASTIN trial, researchers conducted an adaptive phase 2 dose response trial to determine whether a neutrophil inhibitory factor improved recovery in patients with acute ischemic stroke; it did not. However, this trial needed to enroll 966 patients, compared with the need to enroll 1080 patients if a traditional design had been used. Furthermore, the adaptive design made it possible to stop the trial early for futility.1

  
  
• Adaptive Clinical Trials: A Partial Remedy for the Therapeutic Misconception?Adaptive Clinical Trials
  • JAMA: The Journal of the American Medical Association, Vol. 307 (22), pp. 2377-2378, 2012 (commentaire en libre accès)
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  Ces deux articles analysent les enjeux associés aux essais cliniques de type adaptatif pour la recherche de nouveaux traitements

  “Adaptive Clinical Trials: A Partial Remedy for the Therapeutic Misconception?Adaptive Clinical Trials”

  • Meurer, William J. ; Lewis, Roger J. ; Berry, Donald A.

  There is a common “therapeutic misconception” among patients considering participation in clinical trials.1 Some trial participants and family members believe that the goal of a clinical trial is to improve their outcomes—a misperception often reinforced by media advertising of clinical research.2 Clinical trials have primarily scientific aims and rarely attempt to collectively improve the outcomes of their participants. The overarching goal of most clinical trials is to evaluate the effect of a treatment on disease outcomes.3 Comparisons are usually made with placebo for conditions having no established treatments and with standard care for conditions having effective treatments. Any benefit to an individual trial participant is a chance effect of randomization and the true, but unknown, relative effects of the treatments. Available evidence is conflicting regarding whether patients receive some benefit from simply participating in a clinical trial.3 Thus, even though serving ...

  
  

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

A partir de données portant sur 570 patients inclus dans 24 essais cliniques de phase I conduits au Centre MD Anderson entre 2004 et 2009, cette étude met en évidence une corrélation linéaire entre l'évolution de la tumeur mesurée par les critères RECIST et la survie globale des patients

• Change in Tumor Size by RECIST Correlates Linearly With Overall Survival in Phase I Oncology Studies
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  A partir de données portant sur 570 patients inclus dans 24 essais cliniques de phase I conduits au Centre MD Anderson entre 2004 et 2009, cette étude met en évidence une corrélation linéaire entre l'évolution de la tumeur mesurée par les critères RECIST et la survie globale des patients

  “Change in Tumor Size by RECIST Correlates Linearly With Overall Survival in Phase I Oncology Studies”

  • Jain, Rajul K.;Lee, J. Jack;Ng, Chaan;Hong, David;Gong, Jing;Naing, Aung;Wheler, Jennifer;Kurzrock, Razelle

  Purpose RECIST is used to quantify tumor changes during exposure to anticancer agents. Responses are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Clinical trials dictate a patient's management options based on the category into which his or her response falls. However, the association between response and survival is not well studied in the early trial setting.Patients And methods To study the correlation between response as quantified by RECIST and overall survival (OS, the gold-standard survival outcome), we analyzed 570 participants of 24 phase I trials conducted between October 2004 and May 2009, of whom 468 had quantifiable changes in tumor size. Analyses of Kaplan-Meier estimates of OS by response and null Martingale residuals of Cox models were the primary outcome measures. All analyses are landmark analyses.Results Kaplan-Meier analyses revealed strong associations between change in tumor size by RECIST and ...

  
  

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

Cet article passe en revue les arguments qui, d'un point de vue évolutionniste, permettent de rendre compte de l'apparition d'une résistance à une thérapie ciblée

• Evolutionary dynamics of carcinogenesis and why targeted therapy does not work
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
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  Cet article passe en revue les arguments qui, d'un point de vue évolutionniste, permettent de rendre compte de l'apparition d'une résistance à une thérapie ciblée

  “Evolutionary dynamics of carcinogenesis and why targeted therapy does not work”

  • Gillies, Robert J.;Verduzco, Daniel;Gatenby, Robert A.

  All malignant cancers, whether inherited or sporadic, are fundamentally governed by Darwinian dynamics. The process of carcinogenesis requires genetic instability and highly selective local microenvironments, the combination of which promotes somatic evolution. These microenvironmental forces, specifically hypoxia, acidosis and reactive oxygen species, are not only highly selective, but are also able to induce genetic instability. As a result, malignant cancers are dynamically evolving clades of cells living in distinct microhabitats that almost certainly ensure the emergence of therapy-resistant populations. Cytotoxic cancer therapies also impose intense evolutionary selection pressures on the surviving cells and thus increase the evolutionary rate. Importantly, the principles of Darwinian dynamics also embody fundamental principles that can illuminate strategies for the successful management of cancer.

  
  

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