Menée à partir de données portant sur 2 835 patients présentant une tumeur épithéliale récidivante du thymus, cette étude japonaise évalue, du point de vue des taux de survie à 5 et 10 ans après récidive, l'efficacité des traitements chirurgicaux

Surgical management of recurrent thymic epithelial tumors : A retrospective analysis based on the Japanese nationwide database

Mizuno, Tetsuya ; Okumura, Meinoshin ; Asamura, Hisao ; Yoshida, Kazuo ; Niwa, Hiroshi ; Kondo, Kazuya ; Horio, Hirotoshi ; Matsumura, Akihide ; Yokoi, Kohei ; for the Japanese Association for Research on the Thymus

Background : There is no standard treatment for recurrent thymic epithelial tumors. Although the efficacy has not been validated based on the large series studies, surgical resection is sometimes employed for patients with recurrent thymic tumors. The aim of this study is to evaluate the surgical outcomes for recurrent thymic epithelial tumors based on the Japanese nationwide database. Methods : From the database of patients whose thymic epithelial tumors were treated surgically from 1991 [...]

Menée sur 465 patients pédiatriques atteints d'un sarcome d'Ewing osseux de stade localisé, cette étude compare les effets de différentes stratégies thérapeutiques (traitement chirurgical et/ou radiothérapie) sur le contrôle de la maladie et la survie des patients

Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: A report from the Children's Oncology Group

DuBois, Steven G. ; Krailo, Mark D. ; Gebhardt, Mark C. ; Donaldson, Sarah S. ; Marcus, Karen J. ; Dormans, John ; Shamberger, Robert C. ; Sailer, Scott ; Nicholas, Richard W. ; Healey, John H. ; Tarbell, Nancy J. ; Randall, R. Lor ; Devidas, Meenakshi ; Meyer, James S. ; Granowetter, Linda ; Womer, Richard B. ; Bernstein, Mark ; Marina, Neyssa ; Grier, Holcombe E.

BACKGROUND : Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear. METHODS :Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models [...]

Menée sur 612 patients atteints d'un carcinome basocellulaire du visage récidivant ou à haut risque de récidive et traités entre 1999 et 2002, cet essai évalue, du point de vue du taux cumulé de récidive à 10 ans, l'efficacité d'une exérèse chirurgicale et d'un traitement par chirurgie micrographique de Mohs

Surgical excision versus Mohs’ micrographic surgery for basal cell carcinoma of the face: A randomised clinical trial with 10 year follow-up

van Loo, Eva ; Mosterd, Klara ; Krekels, Gertruud A. M. ; Roozeboom, Marieke H. ; Ostertag, Judith U. ; Dirksen, Carmen D. ; Steijlen, Peter M. ; Neumann, H. A. Martino ; Nelemans, Patty J. ; Kelleners-Smeets, Nicole W. J.

Background : Basal cell carcinoma (BCC) is the most common form of cancer among Caucasians and its incidence continues to rise. Surgical excision (SE) is considered standard treatment, though randomised trials with long-term follow-up are rare. We now report the long-term results of a randomised trial comparing surgical excision with Mohs’ micrographic surgery (MMS) for facial BCC. Methods : 408 facial, high risk (diameter at least 1 cm, H-zone location or aggressive histological subtype) [...]

Menée en Chine à partir des données de registres médicaux portant sur 23 patients atteints d'une tumeur thoracique (âge médian des patients : 58 ans ; durée médiane de suivi : 14 mois), cette étude évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et les effets secondaires d'une radiothérapie stéréotaxique corporelle pour traiter une métastase isolée du poumon après lobectomie pulmonaire

Stereotactic body radiation therapy for post-pulmonary lobectomy isolated lung metastasis of thoracic tumor: survival and side effects

Xiong, Weijie ; Xu, Qingfeng ; Xu, Yong ; Sun, Changjin ; Li, Na ; Zhou, Lin ; Liu, Yongmei ; Zhou, Xiaojuan ; Wang, Yongsheng ; Wang, Jin ; Bai, Sen ; Lu, You ; Gong, Youling

Background : Stereotactic body radiation therapy (SBRT) has emerged as an alternative treatment for patients with early stage non-small cell lung cancer (NSCLC) or metastatic pulmonary tumors. However, for isolated lung metastasis (ILM) of thoracic malignances after pulmonary lobectomy, reported outcomes of SBRT have been limited. This study evaluates the role of SBRT in the treatment of such patients. Methods : A retrospective search of the SBRT database was conducted in three hospitals. The [...]

Menée à partir des données de registres médicaux portant sur 154 patientes âgées de 80 ans ou plus et atteintes d'un cancer du sein de stade précoce traité par chirurgie entre 2000 et 2008 (durée médiane de suivi : 5,3 ans), cette étude identifie les facteurs clinicopathologiques associés à la survie spécifique, puis détermine le traitement chirurgical le plus approprié pour ces patientes

Surgical treatment of breast cancer in patients aged 80 years or older - how much is enough?

Besic, Nikola ; Besic, Hana ; Peric, Barbara ; Pilko, Gasper ; Petric, Rok ; Zmuc, Jan ; Dzodic, Radan ; Perhavec, Andraz

Background : The population of elderly people is increasing and so is the population of breast cancer patients aged >=80 years. The aim of our retrospective study was to identify independent prognostic factors for the duration of breast cancer-specific survival of surgically treated patients aged >=80 years. The secondary aim was to determine the appropriate surgical treatment of breast cancer in patients aged >=80 years. Methods : We reviewed the medical records of 154 patients aged >=80 years [...]

Menée in vitro, in vivo et à l'aide de 46 échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude suggère l'intérêt des inhibiteurs de MEK pour le traitement des patients dont les tumeurs présentent des mutations du gène MEK1

MEK inhibitor for gastric cancer with MEK1 gene mutations

Sogabe, Shunsuke ; Togashi, Yosuke ; Kato, Hiroaki ; Kogita, Akihiro ; Mizukami, Takuro ; Sakamoto, Yoichi ; Banno, Eri ; Terashima, Masato ; Hayashi, Hidetoshi ; De Velasco, Marco A ; Sakai, Kazuko ; Fujita, Yoshihiko ; Tomida, Shuta ; Yasuda, Takushi ; Takeyama, Yoshifumi ; Okuno, Kiyotaka ; Nishio, Kazuto

The prognosis for patients with unresectable advanced or recurrent gastric cancer (GC) remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations and upon which the growth of cancer cells is dependent is needed. In this study, we evaluated the sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several GC cell lines in vitro and found three poorly differentiated GC cell lines that were hypersensitive to [...]

Menée sur des lignées cellulaires de cancer de l'estomac avec amplification de FGFR2, cette étude évalue l'activité antitumorale du pazopanib

Pazopanib, a novel multi-targeted kinase inhibitor, shows potent in vitro antitumor activity in gastric cancer cell lines with FGFR2 amplification

Kim, Seung Tae ; Jang, Hye-Lim ; Lee, Su Jin ; Lee, Jeeyun ; Choi, Yoon-La ; Kim, Kyoung-Mee ; Cho, Jeonghee ; Park, Se Hoon ; Park, Young Suk ; Lim, Ho Yeong ; Yashiro, Masakazu ; Kang, Won Ki ; Park, Joon Oh

Pazopanib is an orally bioavailable, ATP-competitive, multi-targeted kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biological sequences of pazopanib activities beyond anti-angiogenesis are poorly defined. We used a panel of 38 GC cell lines in order to test the efficacy of pazopanib. In a growth inhibition assay, genomic changes indicated that pazopanib had differential effects on cell growth. Treatment of the KATO-III, OCUM-2M, SNU-16 and HSC-39 GC cell lines [...]

Menée sur des lignées cellulaires de carcinome hépatocellulaire et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un anticorps ciblant le précurseur de la granuline-épithéline en combinaison avec du cisplatine

Antibody Against Granulin-Epithelin Precursor Sensitizes Hepatocellular Carcinoma to Chemotherapeutic Agents

Wong, Nicholas C.L. ; Cheung, Phyllis F.Y. ; Yip, Chi Wai ; Chan, Kui Fat ; Ng, Irene Oi-Lin ; Fan, Sheung Tat ; Cheung, Siu Tim

Granulin-epithelin precursor (GEP) over-expression has been shown in many cancers with functional role on growth, and recently on regulating chemo-resistance and cancer stem cell properties. Here, we investigate the combined effect of GEP antibody and chemotherapeutic agent. Combination therapy was compared with monotherapy using hepatocellular carcinoma (HCC) cells in vitro and orthotopic liver tumor models in vivo. CD133 and related hepatic cancer stem cell marker expressions were [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, dans le micro-environnement tumoral, le facteur dérivé des macrophages TNF-alpha favorise la résistance à un inhibiteur de MAPK dans le traitement d'un mélanome

The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNFα

Smith, Michael P. ; Sanchez-Laorden, Berta ; O'Brien, Kate ; Brunton, Holly ; Ferguson, Jennifer ; Young, Helen ; Dhomen, Nathalie ; Flaherty, Keith T. ; Frederick, Dennie T. ; Cooper, Zachary A. ; Wargo, Jennifer A. ; Marais, Richard ; Wellbrock, Claudia

Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway–targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma growth factor that provides resistance to MAPK pathway [...]

Cet article passe en revue les perspectives offertes par les immunoconjugués pour le développement de thérapies ciblées en oncologie

The development of immunoconjugates for targeted cancer therapy

Smaglo, Brandon G. ; Aldeghaither, Dalal ; Weiner, Louis M.

Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three separate components: an antibody that binds to a cancer cell antigen with high specificity, an effector molecule that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not separate from the antibody during transit and will reliably release the effector to the cancer cell or tumour [...]

Cet article passe en revue les travaux récents sur les mécanismes épigénétiques associés à la résistance thérapeutique en oncologie

Poised epigenetic states and acquired drug resistance in cancer

Brown, Robert ; Curry, Edward ; Magnani, Luca ; Wilhelm-Benartzi, Charlotte S. ; Borley, Jane

Epigenetic events, which are somatically inherited through cell division, are potential drivers of acquired drug resistance in cancer. The high rate of epigenetic change in tumours generates diversity in gene expression patterns that can rapidly evolve through drug selection during treatment, leading to the development of acquired resistance. This will potentially confound stratified chemotherapy decisions that are solely based on mutation biomarkers. Poised epigenetic states in tumour cells [...]

Cet article passe en revue les travaux récents sur les mécanismes épigénétiques associés à la réponse à l'acide tout-trans rétinoïque dans le traitement d'une leucémie promyélocytaire aiguë

Epigenetics in acute promyelocytic leukaemia pathogenesis and treatment response: A TRAnsition to targeted therapies

Arteaga, M. F. ; Mikesch, J. H. ; Fung, T. K. ; So, C. W. E.

Transcriptional deregulation plays a key role in a large array of cancers, and successful targeting of oncogenic transcription factors that sustain diseases has been a holy grail in the field. Acute promyelocytic leukaemia (APL) driven by chimeric transcription factors encoding retinoic acid receptor alpha fusions is the paradigm of targeted cancer therapy, in which the application of all-trans retinoic acid (ATRA) treatments have markedly transformed this highly fatal cancer to a highly [...]

Menée in vitro sur des modèles de carcinome de l'ovaire résistant à la chimiothérapie, cette étude évalue l'activité antitumorale du solitomab, un anticorps monoclonal ciblant la molécule d'adhérence cellulaire EpCAM

Solitomab, an epithelial cell adhesion molecule/CD3 bispecific antibody (BiTE), is highly active against primary chemotherapy-resistant ovarian cancer cell lines in vitro and fresh tumor cells ex vivo

English, Diana P. ; Bellone, Stefania ; Schwab, Carlton L. ; Roque, Dana M. ; Lopez, Salvatore ; Bortolomai, Ileana ; Cocco, Emiliano ; Bonazzoli, Elena ; Chatterjee, Sudeshna ; Ratner, Elena ; Silasi, Dan-Arin ; Azodi, Masoud ; Schwartz, Peter E. ; Rutherford, Thomas J. ; Santin, Alessandro D.

BACKGROUND Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. METHODS EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines [...]

Menée in vitro et in vivo, cette étude suggère l'intérêt du calcipotriol, un ligand du récepteur de la vitamine D, pour améliorer l'efficacité d'une chimiothérapie chez les patients atteints d'un adénocarcinome canalaire du pancréas

Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

Sherman, Mara H ; Yu, Ruth T ; Engle, Dannielle D ; Ding, Ning ; Atkins, Annette R ; Tiriac, Herve ; Collisson, Eric A ; Connor, Frances ; Van Dyke, Terry ; Kozlov, Serguei ; Martin, Philip ; Tseng, Tiffany W ; Dawson, David W ; Donahue, Timothy R ; Masamune, Atsushi ; Shimosegawa, Tooru ; Apte, Minoti V ; Wilson, Jeremy S ; Ng, Beverly ; Lau, Sue Lynn ; Gunton, Jenny E ; Wahl, Geoffrey M ; Hunter, Tony ; Drebin, Jeffrey A ; O’Dwyer, Peter J ; Liddle, Christopher ; Tuveson, David A ; Downes, Michael ; Evans, Ronald M

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in [...]

Menée in vitro et in vivo sur des modèles de cancer métastatique du sein, cette étude évalue l'activité antitumorale d'un nouveau conjugué anticorps-médicament appelé SGN-LIV1A

SGN-LIV1A: A Novel Antibody-Drug Conjugate Targeting LIV-1 for the Treatment of Metastatic Breast Cancer

Sussman, Django ; Smith, Leia M ; Anderson, Martha E. ; Duniho, Steve ; Hunter, Joshua H ; Kostner, Heather ; Miyamoto, Jamie B ; Nesterova, Albina ; Westendorf, Lori ; Van Epps, Heather A ; Whiting, Nancy ; Benjamin, Dennis R

In this manuscript we describe a novel antibody-drug conjugate (SGN-LIV1A), targeting the zinc transporter LIV-1 (SLC39A6) for the treatment of metastatic breast cancer. LIV-1 was previously known to be expressed by estrogen receptor-positive breast cancers. In this study, we show that LIV-1 expression is maintained after hormonal therapy in primary and metastatic sites and is also up regulated in triple-negative breast cancers. In addition to breast cancer, other indications showing LIV-1 [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de tumeurs du sein surexprimant un fragment de HER2 (p95HER2/611CTF), cette étude évalue la réponse à une chimiothérapie et au trastuzumab

Effect of p95HER2/611CTF on the Response to Trastuzumab and Chemotherapy

Parra-Palau, Josep Lluís ; Morancho, Beatriz ; Peg, Vicente ; Escorihuela, Marta ; Scaltriti, Maurizio ; Vicario, Rocio ; Zacarias-Fluck, Mariano ; Pedersen, Kim ; Pandiella, Atanasio ; Nuciforo, Paolo ; Serra, Violeta ; Cortés, Javier ; Baselga, Jose ; Perou, Charles M. ; Prat, Aleix ; Rubio, Isabel T. ; Arribas, Joaquín

Human epidermal growth factor receptor 2 (HER2)–positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this [...]

Menée in vitro, cette étude met en évidence le rôle joué par l'endoxifène dans l'efficacité thérapeutique du tamoxifène chez les patientes atteintes d'un cancer du sein après la ménopause

Pharmacological Relevance of Endoxifen in a Laboratory Simulation of Breast Cancer in Postmenopausal Patients

Maximov, Philipp Y. ; McDaniel, Russell E. ; Fernandes, Daphne J. ; Bhatta, Puspanjali ; Korostyshevskiy, Valeriy R. ; Curpan, Ramona F. ; Jordan, V. Craig

Background : Tamoxifen is metabolically activated via a CYP2D6 enzyme system to the more potent hydroxylated derivatives 4-hydroxytamoxifen and endoxifen. This study addresses the pharmacological importance of endoxifen by simulating clinical scenarios in vitro. Methods : Clinical levels of tamoxifen metabolites in postmenopausal breast cancer patients previously genotyped for CYP2D6 were used in vitro along with clinical estrogen levels (estrone and estradiol) in postmenopausal patients [...]

Menée in vivo, cette étude suggère l'intérêt d'un inhibiteur de la cathepsine K, appelé L-235, pour la prévention et le traitement des métastases osseuses d'un cancer du sein

Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Duong, Le T. ; Wesolowski, Gregg A ; Leung, Patrick ; Oballa, Renata ; Pickarski, Maureen

Cathepsin K (CatK) is essential for osteoclast mediated bone resorption. CatK expression is also detected in breast cancer (BrCa) cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30 and 100mg/kg, p.o., b.i.d.) or treatment regimen (30mg/kg) was compared to the bisphosphonate zoledronic acid (ZOL, 7.5microg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden and local [...]

Menée sur des lignées cellulaires de carcinome séreux de l'utérus et à l'aide de xénogreffes, cette étude met en évidence l'activité antitumorale de l'afitinib lorsque les tumeurs surexpriment HER2 et ont développé une résistance aux chimiothérapies

Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo

Schwab, C. L. ; Bellone, S. ; English, D. P. ; Roque, D. M. ; Lopez, S. ; Cocco, E. ; Nicoletti, R. ; Bortolomai, I. ; Bonazzoli, E. ; Ratner, E. ; Silasi, D. A. ; Azodi, M. ; Schwartz, P. E. ; Rutherford, T. J. ; Santin, A. D.

Background: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. Methods: Eight of fifteen primary USC cell lines (four with HER2 [...]

Mené sur 30 patients atteints d'une tumeur solide de stade avancé réfractaire aux traitements de référence, cet essai de phase I évalue la dose maximale tolérée, l'activité antitumorale et la toxicité d'un traitement combinant le cixutumumab, un anticorps anti-IGF-1R, et le selumetinib, un inhibiteur de MEK 1/2

A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours

Wilky, B. A. ; Rudek, M. A. ; Ahmed, S. ; Laheru, D. A. ; Cosgrove, D. ; Donehower, R. C. ; Nelkin, B. ; Ball, D. ; Doyle, L. A. ; Chen, H. ; Ye, X. ; Bigley, G. ; Womack, C. ; Azad, N. S.

Background: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Methods: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the [...]

Mené sur 619 patients atteints d'un lymphome agressif réfractaire ou récidivant, cet essai randomisé compare l'efficacité, du point de vue du taux de réponse après deux cycles de traitement et du taux de greffe, et la toxicité de deux combinaisons, gemcitabine-dexaméthasone-cisplatine et dexaméthasone-cytarabine-cisplatine, avant une greffe autologue de cellules souches

Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY.12

Crump, Michael ; Kuruvilla, John ; Couban, Stephen ; MacDonald, David A. ; Kukreti, Vishal ; Kouroukis, C. Tom ; Rubinger, Morel ; Buckstein, Rena ; Imrie, Kevin R. ; Federico, Massimo ; Di Renzo, Nicola ; Howson-Jan, Kang ; Baetz, Tara ; Kaizer, Leonard ; Voralia, Michael ; Olney, Harold J. ; Turner, A. Robert ; Sussman, Jonathan ; Hay, Annette E. ; Djurfeldt, Marina S. ; Meyer, Ralph M. ; Chen, Bingshu E. ; Shepherd, Lois E.

Purpose : For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. Patients and Methods : We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received [...]

Mené sur 423 patients atteints d'un mélanome de stade IIIC ou IV présentant une mutation V600E ou V600K du gène BRAF, cet essai randomisé international évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du trametinib, un inhibiteur de MEK, au dabrafenib, un inhibiteur de BRAF

Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

Long, Georgina V. ; Stroyakovskiy, Daniil ; Gogas, Helen ; Levchenko, Evgeny ; de Braud, Filippo ; Larkin, James ; Garbe, Claus ; Jouary, Thomas ; Hauschild, Axel ; Grob, Jean Jacques ; Sileni, Vanna Chiarion ; Lebbé, Celeste ; Mandalà, Mario ; Millward, Michael ; Arance, Ana ; Bondarenko, Igor ; Haanen, John B.A.G. ; Hansson, Johan ; Utikal, Jochen ; Ferraresi, Virginia ; Kovalenko, Nadezhda ; Mohr, Peter ; Probachai, Volodymyr ; Schadendorf, Dirk ; Nathan, Paul ; Robert, Caroline ; Ribas, Antoni ; DeMarini, Douglas J. ; Irani, Jhangir G. ; Casey, Michelle ; Ouellet, Daniele ; Martin, Anne-Marie ; Le, Ngocdiep ; Patel, Kiran ; Flaherty, Keith

BACKGROUND : Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS : In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) [...]

Mené sur 36 patients atteints d'un mélanome de stade avancé, cet essai multicentrique de phase II évalue l'activité antitumorale et la toxicité d'un composé appelé RO4929097, un inhibiteur de la signalisation Notch

Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933

Lee, Sylvia M. ; Moon, James ; Redman, Bruce G. ; Chidiac, Tarek ; Flaherty, Lawrence E. ; Zha, Yuanyuan ; Othus, Megan ; Ribas, Antoni ; Sondak, Vernon K. ; Gajewski, Thomas F. ; Margolin, Kim A.

BACKGROUND Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per [...]

Mené sur 495 patients atteints d'un mélanome de stade métastatique ou localement avancé présentant la mutation V600E du gène BRAF, cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du cobimetinib, un inhibiteur de MEK, au vemurafenib, un inhibiteur de BRAF

Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma

Larkin, James ; Ascierto, Paolo A. ; Dréno, Brigitte ; Atkinson, Victoria ; Liszkay, Gabriella ; Maio, Michele ; Mandalà, Mario ; Demidov, Lev ; Stroyakovskiy, Daniil ; Thomas, Luc ; Merino, Luis de la Cruz ; Dutriaux, Caroline ; Garbe, Claus ; Sovak, Mika A. ; Chang, Ilsung ; Choong, Nicholas ; Hack, Stephen P. ; McArthur, Grant A. ; Ribas, Antoni

BACKGROUND : The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS : We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation–positive melanoma to receive [...]

Mené sur 71 patients atteints d'un cancer métastatique du pancréas, cet essai randomisé de phase II évalue l'efficacité, du point de vue de la survie globale, et la toxicité d'une stratégie consistant à augmenter les doses de l'erlotinib en combinaison avec la gemcitabine

Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study

Van Cutsem, E. ; Li, C. P. ; Nowara, E. ; Aprile, G. ; Moore, M. ; Federowicz, I. ; Van Laethem, J. L. ; Hsu, C. ; Tham, C. K. ; Stemmer, S. M. ; Lipp, R. ; Zeaiter, A. ; Fittipaldo, A. ; Csutor, Z. ; Klughammer, B. ; Meng, X. ; Ciuleanu, T.

Background: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose. Methods: After a 4-week run-in period (gemcitabine 1000 mg m−2 once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 [...]

Mené sur 50 patients atteints d'un cancer du poumon non à petites cellules de stade avancé présentant un réarrangement du gène ROS1, cet essai évalue l'activité antitumorale et la toxicité du crizotinib

Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer

Shaw, Alice T. ; Ou, Sai-Hong I. ; Bang, Yung-Jue ; Camidge, D. Ross ; Solomon, Benjamin J. ; Salgia, Ravi ; Riely, Gregory J. ; Varella-Garcia, Marileila ; Shapiro, Geoffrey I. ; Costa, Daniel B. ; Doebele, Robert C. ; Le, Long Phi ; Zheng, Zongli ; Tan, Weiwei ; Stephenson, Patricia ; Shreeve, S. Martin ; Tye, Lesley M. ; Christensen, James G. ; Wilner, Keith D. ; Clark, Jeffrey W. ; Iafrate, A. John

BACKGROUND : Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non–small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS : We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 [...]

Mené sur 284 patientes atteintes d'un cancer métastatique du sein HER2-, cet essai randomisé international de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout de capécitabine au bevacizumab en traitement d'entretien après un traitement initial combinant bevacizumab et docétaxel

Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial

Gligorov, Joseph ; Doval, Dinesh ; Bines, José ; Alba, Emilio ; Cortes, Paulo ; Pierga, Jean-Yves ; Gupta, Vineet ; Costa, Rômulo ; Srock, Stefanie ; de Ducla, Sabine ; Freudensprung, Ulrich ; Mustacchi, Giorgio

Background : Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. Methods : We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients [...]

A partir de données portant sur 106 patientes atteintes d'un cancer métastatique du sein triplement négatif et ayant été incluses dans un essai de phase I au Centre MD Anderson entre août 2005 et mai 2012, cette étude identifie l'efficacité de traitements combinant une chimiothérapie, un inhibiteur de l'angiogenèse et/ou un inhibiteur des signalisations PI3K/AKT/mTOR

Triple Negative Breast Cancer Patients Treated at MD Anderson Cancer Center in Phase I Trials: Improved Outcomes with Combination Chemotherapy and Targeted Agents

Ganesan, Prasanth ; Moulder, Stacy ; Lee, J. Jack ; Janku, Filip ; Valero, Vicente ; Zinner, Ralph G. ; Naing, Aung ; Fu, Siqing ; Tsimberidou, Apostolia M. ; Hong, David ; Stephen, Bettzy ; Stephens, Philip ; Yelensky, Roman ; Meric-Bernstam, Funda ; Kurzrock, Razelle ; Wheler, Jennifer J.

Patients with metastatic triple negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson between August 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (n=1); partial response (n=7); or, stable disease ≥6 months (n=4). Patients treated on matched therapy (n=16) compared to [...]

Mené sur 42 patientes atteintes d'un cancer du sein de stade localement avancé ou métastatique ayant progressé après deux lignes de chimiothérapie, cet essai de phase I/II évalue la toxicité et l'activité antitumorale d'un conjugué anticorps-médicament appelé glembatumumab vedotin

Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Locally Advanced or Metastatic Breast Cancer

Bendell, Johanna ; Saleh, Mansoor ; Rose, April A.N. ; Siegel, Peter M. ; Hart, Lowell ; Sirpal, Surendra ; Jones, Suzanne ; Green, Jennifer ; Crowley, Elizabeth ; Simantov, Ronit ; Keler, Tibor ; Davis, Thomas ; Vahdat, Linda

Purpose : Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to [...]

Mené sur 27 patients atteints d'un cancer du poumon non à petites cellules de stade III, cet essai de phase I/II évalue, du point de vue du taux de survie à 1 an et du degré de toxicité, l'intérêt d'ajouter le bortézomib à une chimiothérapie par paclitaxel-carboplatine en combinaison avec une radiothérapie thoracique concomitante

A Phase I/II Study of Bortezomib in Combination with Paclitaxel, Carboplatin and Concurrent Thoracic Radiation Therapy for Non-Small Cell Lung Cancer: NCCTG-N0321

Zhao, Yujie ; Foster, Nathan R. ; Meyers, Jeffrey P. ; Thomas, Sachdev P. ; Northfelt, Donald W. ; Rowland, Kendrith M. Jr. ; Mattar, Bassam I. ; Johnson, David B. ; Molina, Julian R. ; Mandrekar, Sumithra J. ; Schild, Steven E. ; Bearden, James D. III ; Aubry, Marie-Christine ; Adjei, Alex A.

Introduction : Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III NSCLC was evaluated in this phase I/ II study. Methods : Patients with histologic or cytologic [...]

Menée sur 209 patients atteints d'un glioblastome multiforme (âge inférieur à 70 ans), cette étude évalue, par rapport à une radiothérapie à dose standard et du point de vue des taux actuariels de survie sans progression et de survie globale à 5 ans, l'efficacité d'une radiothérapie à haute dose de rayonnements en combinaison avec une chimiothérapie concomitante par témozolomide

Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

Badiyan, Shahed N. ; Markovina, Stephanie ; Simpson, Joseph R. ; Robinson, Clifford G. ; DeWees, Todd ; Tran, David D. ; Linette, Gerry ; Jalalizadeh, Rohan ; Dacey, Ralph ; Rich, Keith M. ; Chicoine, Michael R. ; Dowling, Joshua L. ; Leuthardt, Eric C. ; Zipfel, Gregory J. ; Kim, Albert H. ; Huang, Jiayi

Purpose : To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials : Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was [...]

Mené sur 271 patients atteints d'un rhabdomyosarcome récemment diagnostiqué et à faible risque de récidive (durée médiane de suivi : 4,3 ans), cet essai évalue l'effet, sur le taux de survie sans échec ou le taux de survie globale, d'une réduction de la durée d'un traitement par vincristine, dactinomycine et faible dose de cyclophosphamide en combinaison ou non avec une radiothérapie

Shorter-Duration Therapy Using Vincristine, Dactinomycin, and Lower-Dose Cyclophosphamide With or Without Radiotherapy for Patients With Newly Diagnosed Low-Risk Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group

Walterhouse, David O. ; Pappo, Alberto S. ; Meza, Jane L. ; Breneman, John C. ; Hayes-Jordan, Andrea A. ; Parham, David M. ; Cripe, Timothy P. ; Anderson, James R. ; Meyer, William H. ; Hawkins, Douglas S.

Purpose : Intergroup Rhabdomyosarcoma Study Group (IRSG) studies III and IV showed improved failure-free survival (FFS) rates with vincristine, dactinomycin, and cyclophosphamide (VAC; total cumulative cyclophosphamide dose, 26.4 g/m2) compared with vincristine and dactinomycin (VA) for patients with subset-one low-risk embryonal rhabdomyosarcoma (ERMS; stage 1/2 group I/II ERMS or stage 1 group III orbit ERMS). The objective of Children's Oncology Group ARST0331 was to reduce the length of [...]