Menée in vitro et à l'aide d'une xénogreffe de carcinome hépatocellulaire sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'expression de HAb18G/CD147 confère une radiorésistance aux cellules tumorales en agissant sur la voie de signalisation de l'intégrine bêta

HAb18G/CD147 promotes radioresistance in hepatocellular carcinoma cells: a potential role for integrin β1 signaling

Wu, Jiao ; Li, Yong ; Dang, Ya-Zheng ; Gao, Hong-Xiang ; Jiang, Jian-Li ; Chen, Zhi-Nan

Radiotherapy has played a limited role in the treatment of hepatocellular carcinoma (HCC) due to the risk of tumor radioresistance. A previous study in our lab confirmed that CD147 interacts with integrin β1 and plays an important role in modulating the malignant properties of HCC cells. In this study, we further evaluated the role of CD147 in the radioresistance of HCC and as a potential target for improving radiosensitivity. Upon irradiation, the colony formation, apoptosis, cell cycle [...]

Menée à partir de données portant sur 748 patients ayant survécu à un cancer pédiatrique (âge moyen : 34,2 ans), cette étude évalue la prévalence d'insuffisances hypophysaires après une radiothérapie crânienne, identifie les facteurs de risque associés, puis évalue l'effet du non traitement de ces insuffisances hypophysaires sur la santé des patients

Anterior Hypopituitarism in Adult Survivors of Childhood Cancers Treated With Cranial Radiotherapy: A Report From the St Jude Lifetime Cohort Study

Chemaitilly, Wassim ; Li, Zhenghong ; Huang, Sujuan ; Ness, Kirsten K. ; Clark, Karen L. ; Green, Daniel M. ; Barnes, Nicole ; Armstrong, Gregory T. ; Krasin, Matthew J. ; Srivastava, Deo Kumar ; Pui, Ching-Hon ; Merchant, Thomas E. ; Kun, Larry E. ; Gajjar, Amar ; Hudson, Melissa M. ; Robison, Leslie L. ; Sklar, Charles A.

Purpose : To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies. Patients and Methods : Retrospective study in an established cohort of CCS with 748 participants treated with CRT [...]

Menée à partir de données portant sur 30 patients octogénaires atteints d'une tumeur pulmonaire (âge médian : 85 ans ; durée médiane de suivi : 13 mois), cette étude évalue la tolérabilité d'une radiothérapie stéréotaxique corporelle ablative

Stereotactic ablative body radiation therapy for tumors in the lung in octogenarians: a retrospective single institution study

Cannon, Nathan ; Iyengar, Puneeth ; Choy, Hak ; Timmerman, Robert ; Meyer, Jeffrey

Background : Treatment of cancer in the lung in octogenarians is limited by their health and functional status. Stereotactic ablative radiotherapy is an established noninvasive treatment option for medically inoperable patients, with a toxicity profile that may be more tolerable in elderly patients. Methods : Patients more than 80 years old treated with stereotactic ablative radiotherapy for malignant tumors in the lung between January 2007 and August 2012 at a single institution were [...]

Menée à partir de données portant sur 40 patients atteints d'une ou plusieurs oligo-métastases pulmonaires ayant pour origine un cancer colorectal, cette étude évalue l'efficacité, du point de vue de la survie globale et de la survie sans progression, et la sécurité d'une radiothérapie stéréotaxique ablative

Stereotactic Ablative Radiation Therapy as First Local Therapy for Lung Oligometastases From Colorectal Cancer: A Single-Institution Cohort Study

Filippi, Andrea Riccardo ; Badellino, Serena ; Ceccarelli, Manuela ; Guarneri, Alessia ; Franco, Pierfrancesco ; Monagheddu, Chiara ; Spadi, Rosella ; Ragona, Riccardo ; Racca, Patrizia ; Ricardi, Umberto

Purpose : To estimate stereotactic ablative radiation therapy (SABR) efficacy and its potential role as an alternative to surgery for the treatment of lung metastases from colorectal cancer. Methods and Materials : Forty consecutive patients who received SABR as first local therapy at the time of lung progression were included, from 2004 to 2014. The primary study endpoint was overall survival. Secondary endpoints were progression-free survival and safety. Results : A single nodule was treated [...]

Menée à partir de données portant sur 11 patients atteints d'un carcinome à cellules rénales avec thrombose de la veine cave inférieure, cette étude évalue la faisabilité et la sécurité d'une néphrectomie radicale en combinaison avec une thrombectomie laparoscopique

Laparoscopic Radical Nephrectomy and Inferior Vena Cava Thrombectomy in the Treatment of Renal Cell Carcinoma

Shao, Pengfei ; Li, Jie ; Qin, Chao ; Lv, Qiang ; Ju, Xiaobing ; Li, Pu ; Shao, Yongfeng ; Ni, Buqing ; Yin, Changjun

Background : Radical nephrectomy with inferior vena cava (IVC) thrombectomy is the preferred treatment for renal cell carcinoma (RCC) with IVC thrombus. However, IVC thrombectomy using a laparoscopic approach has not been reported for high-level thrombi. Objective : To describe the surgical technique for laparoscopic IVC thrombectomy in patients with different thrombus levels and to assess its safety and feasibility. Design, setting, and participants : Retrospective review of medical records [...]

A partir d'une revue systématique de la littérature publiée jusqu'en avril 2014 (105 articles), cette étude évalue l'efficacité, du point de vue de la qualité des marges de résection et des taux de survie à 3 et 5 ans, et les complications fonctionnelles d'une cystectomie radicale assistée par robot, d'une cystectomie radicale laparoscopique et d'une cystectomie radicale par voie ouverte pour traiter un cancer invasif de la vessie

Systematic Review and Cumulative Analysis of Oncologic and Functional Outcomes After Robot-assisted Radical Cystectomy

Yuh, Bertram ; Wilson, Timothy ; Bochner, Bernie ; Chan, Kevin ; Palou, Joan ; Stenzl, Arnulf ; Montorsi, Francesco ; Thalmann, George ; Guru, Khurshid ; Catto, James W. F. ; Wiklund, Peter N. ; Novara, Giacomo

Context : Although open radical cystectomy (ORC) is still the standard approach, laparoscopic radical cystectomy (LRC) and robot-assisted radical cystectomy (RARC) are increasingly performed. Objective : To report on a systematic literature review and cumulative analysis of pathologic, oncologic, and functional outcomes of RARC in comparison with ORC and LRC. Evidence acquisition : Medline, Scopus, and Web of Science databases were searched using a free-text protocol including the terms [...]

Menée à partir de données portant sur 503 patients atteints d'un cancer de la vessie traité entre 2000 et 2013, cette étude multicentrique évalue l'efficacité, du point de vue des taux actuariels de survie sans récidive, de survie spécifique et de survie globale à 5 et 10 ans, et les complications d'une cystectomie radicale par voie laparoscopique

Long-term analysis of oncological outcomes after laparoscopic radical cystectomy in Europe: results from a multicentre study by the European Association of Urology (EAU) section of Uro-technology

Albisinni, Simone ; Rassweiler, Jens ; Abbou, Clement-Claude ; Cathelineau, Xavier ; Chlosta, Piotr ; Fossion, Laurent ; Gaboardi, Franco ; Rimington, Peter ; Salomon, Laurent ; Sanchez-Salas, Rafael ; Stolzenburg, Jens-Uwe ; Teber, Dogu ; van Velthoven, Roland

Objective : To report long-term outcomes of laparoscopic radical cystectomy (LRC) in a multicentre European cohort, and explore feasibility and safety of LRC. Patients and Methods : This study was coordinated by European Association of Urology (EAU)-section of Uro-technology (ESUT) with nine centres enrolling 503 patients undergoing LRC for bladder cancer prospectively between 2000 and 2013. Data were retrospectively analysed. Descriptive statistics were used to explore peri- and postoperative [...]

Cet article passe en revue les différentes méthodes susceptibles d'être mises en oeuvre pour développer des traitements attaquant les tumeurs dans lesquelles des gènes suppresseurs de tumeurs sont inactivés

Therapeutic targeting of tumor suppressor genes

Morris, Luc G. T. ; Chan, Timothy A.

Carcinogenesis is a multistep process attributable to both gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. Currently, most molecular targeted therapies are inhibitors of oncogenes, because inactivated tumor suppressor genes have proven harder to “drug.” Nevertheless, in cancers, tumor suppressor genes undergo alteration more frequently than do oncogenes. In recent years, several promising strategies directed at tumor suppressor genes, or the [...]

Menée in vitro et in vivo, cette étude évalue l'intérêt d'une méthode systématique d'identification de voies de signalisation associées à une résistance thérapeutique

Systematic identification of signaling pathways with potential to confer anticancer drug resistance

Martz, Colin A. ; Ottina, Kathleen A. ; Singleton, Katherine R. ; Jasper, Jeff S. ; Wardell, Suzanne E. ; Peraza-Penton, Ashley ; Anderson, Grace R. ; Winter, Peter S. ; Wang, Tim ; Alley, Holly M. ; Kwong, Lawrence N. ; Cooper, Zachary A. ; Tetzlaff, Michael ; Chen, Pei-Ling ; Rathmell, Jeffrey C. ; Flaherty, Keith T. ; Wargo, Jennifer A. ; McDonnell, Donald P. ; Sabatini, David M. ; Wood, Kris C.

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)–mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la surexpression du micro-ARN miR-155 dans les lymphocytes T spécifiques des tumeurs peut être utilisée pour augmenter l'efficacité des immunothérapies adoptives en évitant un conditionnement par lymphodéplétion

miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines

Ji, Yun ; Wrzesinski, Claudia ; Yu, Zhiya ; Hu, Jinhui ; Gautam, Sanjivan ; Hawk, Nga V. ; Telford, William G. ; Palmer, Douglas C. ; Franco, Zulmarie ; Sukumar, Madhusudhanan ; Roychoudhuri, Rahul ; Clever, David ; Klebanoff, Christopher A. ; Surh, Charles D. ; Waldmann, Thomas A. ; Restifo, Nicholas P. ; Gattinoni, Luca

Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic “cytokine sinks.” These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts [...]

A partir d'échantillons sanguins prélevés sur 32 patients atteints d'une leucémie lymphocytaire chronique primitive, cette étude identifie un ensemble d'antigènes tumoraux associés à la réponse spontanée du système immunitaire et suggère leur intérêt pour développer de nouvelles immunothérapies

HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL)

Kowalewski, Daniel J. ; Schuster, Heiko ; Backert, Linus ; Berlin, Claudia ; Kahn, Stefan ; Kanz, Lothar ; Salih, Helmut R. ; Rammensee, Hans-Georg ; Stevanovic, Stefan ; Stickel, Juliane Sarah

The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell–based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of [...]

Menée in vitro et in vivo, cette étude suggère l'intérêt d'une stratégie à base d'inhibiteurs de BRD4 pour le traitement des patientes atteintes d'un carcinome séreux ovarien de haut grade surexprimant la protéine MYC

An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

Baratta, Maria Giuseppina ; Schinzel, Anna C. ; Zwang, Yaara ; Bandopadhayay, Pratiti ; Bowman-Colin, Christian ; Kutt, Jennifer ; Curtis, Jennifer ; Piao, Huiying ; Wong, Laura C. ; Kung, Andrew L. ; Beroukhim, Rameen ; Bradner, James E. ; Drapkin, Ronny ; Hahn, William C. ; Liu, Joyce F. ; Livingston, David M.

High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les travaux récents sur le cancer du poumon non à petites cellules ALK+

Future options for ALK-positive non-small cell lung cancer

Iacono, Daniela ; Chiari, Rita ; Metro, Giulio ; Bennati, Chiara ; Bellezza, Guido ; Cenci, Matteo ; Ricciuti, Biagio ; Sidoni, Angelo ; Baglivo, Sara ; Minotti, Vincenzo ; Crino, Lucio

Recent advances in the understanding of non-small cell lung cancer (NSCLC) biology have revealed a number of ‘targetable’ genetic alterations that underlie cancer growth and survival in specific patients subgroups. The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a population of NSCLCs in whom dysregulation of ALK-tyrosine kinase (-TK) leads to uncontrolled proliferation of cancer cells, thus providing the basis for the therapeutic use of ALK-TK inhibitors (-TKIs) in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant l'intérêt d'une stratégie combinant l'inhibition de deux isoformes de PI3K et du récepteur des androgènes pour le traitement des patients atteints d'un cancer de la prostate présentant un gène PTEN muté

Feedback Suppression of PI3Kα Signaling in PTEN-Mutated Tumors Is Relieved by Selective Inhibition of PI3Kβ

Schwartz, Sarit ; Wongvipat, John ; Trigwell, Cath B ; Hancox, Urs ; Carver, Brett S ; Rodrik-Outmezguine, Vanessa ; Will, Marie ; Yellen, Paige ; de Stanchina, Elisa ; Baselga, Jose ; Scher, Howard I ; Barry, Simon T ; Sawyers, Charles L ; Chandarlapaty, Sarat ; Rosen, Neal

In PTEN-mutated tumors, we show that PI3K

Mené sur 720 patients atteints d'un carcinome hépatocellulaire avancé, cet essai international de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout du sorafenib à l'erlotinib

SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

Zhu, Andrew X. ; Rosmorduc, Olivier ; Evans, T.R. Jeffry ; Ross, Paul J. ; Santoro, Armando ; Carrilho, Flair Jose ; Bruix, Jordi ; Qin, Shukui ; Thuluvath, Paul J. ; Llovet, Josep M. ; Leberre, Marie-Aude ; Jensen, Markus ; Meinhardt, Gerold ; Kang, Yoon-Koo

Purpose : To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. Patients and Methods : Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). Results : [...]

Mené sur 30 patients atteints d'un carcinome hépatocellulaire avancé, cet essai de phase II évalue l'efficacité, du point de vue du contrôle de la tumeur à 16 semaines, et la toxicité de l'axitinib en traitement de deuxième ligne

A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma

McNamara, Mairéad G. ; Le, Lisa W. ; Horgan, Anne M. ; Aspinall, Alex ; Burak, Kelly W. ; Dhani, Neesha ; Chen, Eric ; Sinaei, Mehrdad ; Lo, Glen ; Kim, Tae Kyoung ; Rogalla, Patrik ; Bathe, Oliver F. ; Knox, Jennifer J.

BACKGROUND Second-line treatment options in advanced hepatocellular carcinoma (HCC) are limited. Axitinib, a selective potent tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor VEGF) receptors 1, 2, and 3, merits exploration in HCC. METHODS This was a single-arm phase II trial of axitinib in advanced HCC. Eligible patients were Child-Pugh A/B7, with measurable progressive disease after TKIs/antiangiogenic drugs. Axitinib was started at 5 mg twice daily orally, titrated from 2 [...]

Mené sur 51 patients atteints d'une leucémie lymphocytaire chronique réfractaire présentant des anomalies d'expression du gène TP53, cet essai de phase II évalue l'efficacité, du point de vue de la réponse thérapeutique à 24 semaines, et la toxicité de l'ibrutinib

Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial

Farooqui, Mohammed Z. H. ; Valdez, Janet ; Martyr, Sabrina ; Aue, Georg ; Saba, Nakhle ; Niemann, Carsten U. ; Herman, Sarah E. M. ; Tian, Xin ; Marti, Gerald ; Soto, Susan ; Hughes, Thomas E. ; Jones, Jade ; Lipsky, Andrew ; Pittaluga, Stefania ; Stetler-Stevenson, Maryalice ; Yuan, Constance ; Lee, Yuh Shan ; Pedersen, Lone B. ; Geisler, Christian H. ; Calvo, Katherine R. ; Arthur, Diane C. ; Maric, Irina ; Childs, Richard ; Young, Neal S. ; Wiestner, Adrian

Background : Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations. Methods : In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical [...]

Mené sur 102 patients atteints d'un lymphome hodgkinien réfractaire/récidivant, cet essai évalue l'efficacité, du point de vue de la survie globale et de la survie sans progression, d'un conjugué anticorps-médicament, le brentuximab vedotin, administré après une greffe autologue de cellules souches (durée médiane de suivi : 3 ans)

Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma

Gopal, Ajay K. ; Chen, Robert ; Smith, Scott E. ; Ansell, Stephen M. ; Rosenblatt, Joseph D. ; Savage, Kerry J. ; Connors, Joseph M. ; Engert, Andreas ; Larsen, Emily K. ; Chi, Xuedong ; Sievers, Eric L. ; Younes, Anas

We present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N=102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission on brentuximab vedotin, [...]

Mené sur 16 patients atteints d'un cancer asymptomatique de la prostate résistant à la castration, cet essai évalue l'intérêt d'injections de testostérone, en combinaison avec l'étoposide, pour surmonter une résistance thérapeutique

Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study

Schweizer, Michael T. ; Antonarakis, Emmanuel S. ; Wang, Hao ; Ajiboye, A. Seun ; Spitz, Avery ; Cao, Haiyi ; Luo, Jun ; Haffner, Michael C. ; Yegnasubramanian, Srinivasan ; Carducci, Michael A. ; Eisenberger, Mario A. ; Isaacs, John T. ; Denmeade, Samuel R.

Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to [...]

Mené sur 406 patientes atteintes d'un cancer du sein HER2+ sans envahissement ganglionnaire dont la plus grande dimension de la tumeur n'excède pas 3cm, cet essai multicentrique évalue l'efficacité, du point de vue de la survie sans maladie invasive, et la toxicité d'un traitement adjuvant combinant paclitaxel et trastuzumab (durée médiane de suivi : 4 ans)

Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer

Tolaney, Sara M. ; Barry, William T. ; Dang, Chau T. ; Yardley, Denise A. ; Moy, Beverly ; Marcom, P. Kelly ; Albain, Kathy S. ; Rugo, Hope S. ; Ellis, Matthew ; Shapira, Iuliana ; Wolff, Antonio C. ; Carey, Lisa A. ; Overmoyer, Beth A. ; Partridge, Ann H. ; Guo, Hao ; Hudis, Clifford A. ; Krop, Ian E. ; Burstein, Harold J. ; Winer, Eric P.

BACKGROUND : No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS : We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly [...]

Mené sur 69 patientes atteintes d'un cancer métastatique du sein HER2+, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression à 6 mois, et la toxicité d'un traitement combinant paclitaxel, trastuzumab et pertuzumab

Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Dang, Chau ; Iyengar, Neil ; Datko, Farrah ; D'Andrea, Gabriella ; Theodoulou, Maria ; Dickler, Maura ; Goldfarb, Shari ; Lake, Diana ; Fasano, Julie ; Fornier, Monica ; Gilewski, Theresa ; Modi, Shanu ; Gajria, Devika ; Moynahan, Mary Ellen ; Hamilton, Nicola ; Patil, Sujata ; Jochelson, Maxine ; Norton, Larry ; Baselga, Jose ; Hudis, Clifford

Purpose : The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods : Patients with metastatic human epidermal growth factor [...]

A partir de données issues de trois essais cliniques ayant évalué le bevacizumab en complément d'une chimiothérapie pour le traitement d'un cancer métastatique du sein, cette étude suggère que, s'ils ne sont pas toxiques en monothérapie, les inhibiteurs de l'angiogenèse augmentent la toxicité d'une chimiothérapie lorsqu'ils sont prescrits en combinaison

The toxicity of anti-VEGF agents when coupled with standard chemotherapeutics

Afranie-Sakyi, Jennifer A. ; Klement, Giannoula Lakka

Bevacizumab (Avastin®, Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit. We compare and analyze the landmark trials [...]

Menée sur un modèle murin, cette étude montre qu'un traitement combinant une radiothérapie et l'interleukine IL2 couplée à L19, une molécule ciblant l'extra-domaine B de la fibronectine (un marqueur de la néo-angiogenèse tumorale), peut avoir des effets antitumoraux durables

Radiotherapy combined with the immunocytokine (L19-IL2) provides long-lasting anti-tumor effects

Zegers, Catharina M.L. ; Rekers, Nicolle H. ; Quaden, Dana H.F. ; Lieuwes, Natasja G ; Yaromina, Ala ; Germeraad, Wilfred T.V. ; Wieten, Lotte ; Biessen, Erik A.L. ; Boon, Louis ; Neri, Dario ; Troost, Esther G.C. ; Dubois, Ludwig J. ; Lambin, Philippe

Purpose : Radiotherapy (RT) modifies the tumor microenvironment and causes the release of tumor antigens, which can enhance the effect of immunotherapy (IT). L19 targets the extra domain B (ED-B) of fibronectin, a marker for tumor neo-angiogenesis, and can be used as immunocytokine when coupled to interleukin-2 (IL2). We hypothesize that RT in combination with L19-IL2 provides an enhanced antitumor effect, which is dependent on ED-B expression. Experimental Design : Mice were injected with [...]

Cet article fait le point sur l'utilisation, l'efficacité et la toxicité d'une radiothérapie avec modulation d'intensité de l'ensemble de la région pelvienne pour traiter des cancers gynécologiques

Whole Pelvic Intensity-modulated Radiotherapy for Gynecological Malignancies: A Review of the Literature

Hymel, Rockne ; Jones, Guy C. ; Simone Ii, Charles B.

Radiation therapy has long played a major role in the treatment of gynecological malignancies. There is increasing interest in the utility of intensity-modulated radiotherapy (IMRT) and its application to treat gynecological malignancies. Herein, we review the state-of-the-art use of IMRT for gynecological malignancies and report how it is being used alone as well as in combination with chemotherapy in both the adjuvant and definitive settings. Based on dosimetric and clinical evidence, IMRT [...]

Cet article passe en revue les échecs des traitements combinant un médicament anti-cancer et une radiothérapie, puis fait le point sur les nouvelles stratégies thérapeutiques et leur efficacité potentielle

Drug Radiotherapy Combinations : Review of previous failures and reasons for future optimism

Higgins, Geoff S. ; O’Cathail, Sean M. ; Muschel, Ruth J. ; McKenna, W. Gillies

Combining chemotherapy with radiotherapy has resulted in significant clinical improvements in many different tumour types. However, the non-specific mechanisms by which these drugs exert their effects mean that this is often at the expense of increased side effects. Previous attempts at using targeted drugs to induce more tumour specific radiosensitisation have been generally disappointing. Although cetuximab, an EGFR monoclonal antibody, resulted in improved overall survival in HNSCC when [...]

Mené sur 49 patients atteints d'un cancer du pancréas de stade localement avancé (âge médian : 67 ans ; durée médiane de suivi : 13,9 mois), cet essai multicentrique de phase II évalue la toxicité gastro-intestinale de la gemcitabine en combinaison avec une radiothérapie corporelle stéréotaxique fractionnée

Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma

Herman, Joseph M. ; Chang, Daniel T. ; Goodman, Karyn A. ; Dholakia, Avani S. ; Raman, Siva P. ; Hacker-Prietz, Amy ; Iacobuzio-Donahue, Christine A. ; Griffith, Mary E. ; Pawlik, Timothy M. ; Pai, Jonathan S. ; O'Reilly, Eileen ; Fisher, George A. ; Wild, Aaron T. ; Rosati, Lauren M. ; Zheng, Lei ; Wolfgang, Christopher L. ; Laheru, Daniel A. ; Columbo, Laurie A. ; Sugar, Elizabeth A. ; Koong, Albert C.

BACKGROUND : This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). METHODS : A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m2) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 [...]

A partir des données de 28 essais incluant 4 352 patients atteints d'un cancer du poumon non à petites cellules de stade localement avancé et non résécable, cette étude compare l'efficacité de différents protocoles de chimioradiothérapie

An updated systematic review of lung chemo-radiotherapy using a new evidence aggregation method

Williams, Matt ; Liu, Zi Wei ; Hunter, Anthony ; Macbeth, Fergus

Objective : The main treatment for locally-advanced, unresectable non-small cell lung cancer (NSCLC) is radical radiotherapy, with or without chemotherapy. Numerous trials have been performed, the results of which often disagree. Despite publication of several systematic reviews, there is not a consensus on practice, and outcomes are poor. To address this problem, we have applied a recently published evidence aggregation method to update the Cochrane Systematic Review (CSR) of lung [...]

Mené sur 105 patients atteints d'un cancer du poumon non à petites cellules et présentant au plus 4 oligo-métastases asymptomatiques du cerveau (âge médian : 58 ans), cet essai de phase III évalue l'intérêt d'une radiochirurgie stéréotaxique cérébrale avant une chimiothérapie pour améliorer la survie globale des patients

A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small cell lung cancer

Lim, S. H. ; Lee, J. Y. ; Lee, M.-Y. ; Kim, H. S. ; Lee, J. ; Sun, J.-M. ; Ahn, J. S. ; Um, S.-W. ; Kim, H. ; Kim, B. S. ; Kim, S. T. ; Na, D. L. ; Sun, J. Y. ; Jung, S. H. ; Park, K. ; Kwon, O. J. ; Lee, J.-I. ; Ahn, M.-J.

Background : It is unclear whether treating brain metastasis before starting systemic chemotherapy can improve survival compared to upfront chemotherapy in non-small cell lung cancer (NSCLC) with asymptomatic cerebral oligo-metastases. Patients and methods : We undertook a randomized controlled trial of 105 patients with one to four brain metastases, admitted to Samsung Medical Center between 2008 and 2013. Patients were randomly assigned to receive stereotactic radiosurgery (SRS) (49 patients) [...]

Menée in vitro et à l'aide d'une xénogreffe de glioblastome humain sur un modèle murin, cette étude identifie des inhibiteurs de kinase Aurora et évalue leur efficacité pour supprimer la radiorésistance des cellules souches tumorales

Radiotherapy followed by aurora kinase inhibition target tumor-propagating cells in human glioblastoma

Li, Nan ; Maly, Dustin J ; Chanthery, Yvan H. ; Sirkis, Daniel W ; Nakamura, Jean L ; Berger, Mitchel S. ; James, C. David ; M. Shokat, Kevan M. ; Weiss, William A. ; Persson, Anders I

Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPCs), resulting in tumor regrowth. To identify kinases that promote TPC self-renewal rather than increasing proliferation in human GBM cultures, we screened a library of 54 non-selective tool compounds and determined their kinase inhibitor profiles in vitro. Most compounds inhibited aurora kinase (AURK) activity and blocked TPC self-renewal, [...]

Cet article présente une proposition d'encadrement réglementaire de l'enregistrement des essais cliniques et de leurs résultats aux Etats-Unis

The Proposed Rule for U.S. Clinical Trial Registration and Results Submission

Zarin, Deborah A. ; Tse, Tony ; Sheehan, Jerry

In this article, we provide information about the FDAAA and NPRM to encourage the research community to submit comments on the proposed rule at www.regulations.gov/#!docketDetail;D=NIH-2011-0003. Comments submitted before February 19, 2015, will be considered in formulating the final rule.

A partir d'une revue de la littérature, cette étude propose aux investigateurs d'essais cliniques en oncologie une liste des médicaments à risque minimal d'interactions

Concomitant drugs with low risks of drug-drug interactions for use in oncology clinical trials

Ranchon, Florence ; Vial, Thierry ; Rioufol, Catherine ; Hénin, Emilie ; Falandry, Claire ; Freyer, Gilles ; Trillet-Lenoir, Véronique ; Le Tourneau, Christophe ; You, Benoit

Background : Drug-Drug Interactions (DDIs) may occur with investigational drugs and affect patient safety, trial outcomes, and drug development. A list of preferred drugs with minimal risks of DDIs for treatment of symptoms or comorbidities frequently encountered by cancer patients would be helpful. Methods : We reviewed the literature to assess DDIs reported for the main drugs available for treatment of symptoms/comorbidities frequently encountered by cancer patients. Reviews and relevant [...]

Cet article passe en revue les travaux récents sur le diagnostic et les traitements d'un myélome multiple

Multiple myeloma

Röllig, Christoph ; Knop, Stefan ; Bornhäuser, Martin

Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in [...]

Cet article passe en revue les enjeux associés au développement de nouveaux critères de jugement de substitution dans le cadre des essais cliniques de traitement d'un cancer du poumon

Developing biomarker-specific end points in lung cancer clinical trials

Neal, Joel W. ; Gainor, Justin F. ; Shaw, Alice T.

In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. [...]

A partir d'échantillons de tumeurs primitives et de métastases cérébrales prélevés sur des patients atteints d'un cancer du poumon non à petites cellules, cette étude évalue l'intérêt de xénogreffes dérivées des patients pour identifier une thérapie ciblée adaptée

Patient-derived xenografts from non-small cell lung cancer brain metastases are valuable translational platforms for the development of personalized targeted therapy

Lee, Hye Won ; Lee, Jung-Il ; Lee, Se Jeong ; Cho, Hyun Jung ; Song, Hye Jin ; Jeong, Da Eun ; Seo, Yun Jee ; Shin, Sang ; Joung, Je-Gun ; Kwon, Yong-Jun ; Choi, Yoon-La ; Park, Woong-Yang ; Lee, Hyun Moo ; Seol, Ho Jun ; Shim, Young Mog ; Joo, Kyeung Min ; Nam, Do-Hyun

Purpose:The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the [...]