Menée sur des lignées cellulaires humaines de cancer du poumon non à petites cellules puis à l'aide d'un modèle murin transgénique et d'une xénogreffe de tumeur humaine, cette étude montre que l'inhibition de la voie de signalisation Hedgehog sensibilise les cellules tumorales aux rayonnements ionisants

Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

Zeng, Jing ; Aziz, Khaled ; Chettiar, Sivarajan T. ; Aftab, Blake T. ; Armour, Michael ; Gajula, Rajendra ; Gandhi, Nishant ; Salih, Tarek ; Herman, Joseph M. ; Wong, John ; Rudin, Charles M. ; Tran, Phuoc T. ; Hales, Russell K.

Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human [...]

Menée sur 53 patientes atteintes d'un cancer de l'endomètre ou d'un cancer du col de l'utérus, cette étude évalue, en fonction de la dose de rayonnements ionisants, la toxicité gastro-intestinale aiguë et retardée d'une radiothérapie avec modulation d'intensité en champs étendus ciblant les ganglions lymphatiques para-aortiques

Duodenal and Other Gastrointestinal Toxicity in Cervical and Endometrial Cancer Treated With Extended-Field Intensity Modulated Radiation Therapy to Paraortic Lymph Nodes

Poorvu, Philip D. ; Sadow, Cheryl A. ; Townamchai, Kanokpis ; Damato, Antonio L. ; Viswanathan, Akila N.

To characterize the rates of acute and late duodenal and other gastrointestinal (GI) toxicities among patients treated for cervical and endometrial cancers with extended-field intensity modulated radiation therapy (EF-IMRT) to the paraortic nodes and to analyze dose-volume relationships of GI toxicities. Fifty-three patients with endometrial or cervical cancer underwent EF-IMRT to the paraortic nodes, of whom 46 met the inclusion criteria for GI toxicity and 45 for duodenal toxicity analysis. [...]

Cet article passe en revue les perspectives offertes par la radiothérapie guidée par l'image pour le traitement des cancers

Image-guided radiotherapy: from current concept to future perspectives

Jaffray, David A.

Radiotherapy is a highly effective, targeted therapy for the management of cancer. Technological innovations have enabled the direct integration of imaging technology into the radiation treatment device to increase the precision and accuracy of radiation delivery. As well as addressing a clinical need to better control the placement of the dose within the body, image-guided radiotherapy has enabled innovators in the field to accelerate their exploration of a number of different paradigms of [...]

Menée sur 30 patients atteints d'un cancer du poumon non à petites cellules de stade IIIA, IIIB ou IV et inopérables (durée médiane de suivi : 13 mois), cette étude évalue, du point de vue de la survie sans progression, de la survie globale à 2 ans et des événements indésirables, l'efficacité et la toxicité d'une radiothérapie tridimensionnelle hypofractionnée guidée par l'image

Image Guided Hypofractionated 3-Dimensional Radiation Therapy in Patients With Inoperable Advanced Stage Non-Small Cell Lung Cancer

Osti, Mattia Falchetto ; Agolli, Linda ; Valeriani, Maurizio ; Falco, Teresa ; Bracci, Stefano ; De Sanctis, Vitaliana ; Maurizi Enrici, Riccardo

Hypofractionated radiation therapy (HypoRT) can potentially improve local control with a higher biological effect and shorter overall treatment time. Response, local control, toxicity rates, and survival rates were evaluated in patients affected by inoperable advanced stage non-small cell lung cancer (NSCLC) who received HypoRT. Thirty patients with advanced NSCLC were enrolled; 27% had stage IIIA, 50% had stage IIIB, and 23% had stage IV disease. All patients underwent HypoRT with a prescribed [...]

Cet article passe en revue les travaux récents sur les anomalies de régulation des voies de réparation des atteintes à l'ADN et leur intérêt pour le développement de thérapies ciblées

DNA repair dysregulation from cancer driver to therapeutic target

Curtin, Nicola J.

Dysregulation of DNA damage repair and signalling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. Dysfunction of one DNA repair pathway may be compensated for by the function of another compensatory DDR pathway, which may be increased and contribute to resistance to DNA-damaging chemotherapy and radiotherapy. Therefore, DDR pathways make an ideal target for therapeutic [...]

Cet article passe en revue les perspectives offertes par le ciblage des anomalies génomiques de protéines méthyltransférases pour le traitement des cancers

Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics

Copeland, R. A. ; Moyer, M. P. ; Richon, V. M.

The human protein methyltransferases (PMTs) constitute a large enzyme class composed of two families, the protein lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). Examples have been reported of both PKMTs and PRMTs that are genetically altered in specific human cancers, and in several cases these alterations have been demonstrated to confer a unique dependence of the cancer cells on PMT enzymatic activity for the tumorigenic phenotype. Examples of such [...]

Menée à l'aide d'un modèle murin, cette étude évalue l'effet d'une inhibition de la glycolyse, en combinaison avec des agents cytotoxiques, sur l'induction d'une mort cellulaire immunogénique

Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

Bénéteau, Marie ; Zunino, Barbara ; Jacquin, Marie A. ; Meynet, Ophélie ; Chiche, Johanna ; Pradelli, Ludivine A. ; Marchetti, Sandrine ; Cornille, Aurore ; Carles, Michel ; Ricci, Jean-Ehrland

Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We [...]

A partir d'échantillons prélevés sur 39 patients atteints d'une leucémie myéloïde aiguë (28 patients en rémission complète après chimiothérapie, 11 patients avec une maladie persistante après chimiothérapie), cette étude montre qu'une leucémie récidivante est toujours liée à la réémergence ou à l'évolution d'un clone fondateur

Clonal evolution and devolution following chemotherapy in adult acute myelogenous leukemia

Parkin, Brian ; Ouillette, Peter ; Li, Yifeng ; Keller, Jennifer ; Lam, Cindy ; Roulston, Diane ; Li, Cheng ; Shedden, Kerby ; Malek, Sami N.

The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete [...]

Menée sur 30 patients atteints d'un myélome multiple, cette étude met én évidence des sous-populations cellulaires impliquées dans la résistance thérapeutique

Clinical drug resistance linked to inter-convertible phenotypic and functional states of tumor-propagating cells in multiple myeloma

Chaidos, Aristeidis ; Barnes, Chris P. ; Cowan, Gillian ; May, Philippa C. ; Melo, Valeria ; Hatjiharissi, Evdoxia ; Papaioannou, Maria ; Harrington, Heather ; Doolittle, Helen ; Terpos, Evangelos ; Dimopoulos, Meletios ; Abdalla, Saad ; Yarranton, Helen ; Naresh, Kikkeri ; Foroni, Letizia ; Reid, Alistair ; Rahemtulla, Amin ; Stumpf, Michael ; Roberts, Irene ; Karadimitris, Anastasios

The phenotype and function of cells enriched in tumor-propagating activity and their relationship to the phenotypic architecture in multiple myeloma (MM) are controversial. Here, in a cohort of 30 patients we show that MM comprises four hierarchically organised, clonally-related sub-populations which, although phenotypically distinct, share the same oncogenic chromosomal abnormalities as well as immunoglobulin heavy chain complementarity region 3 area sequence. Assessed in xenograft assays, [...]

Menée in vitro et in vivo, cette étude évalue l'intérêt d'une stratégie basée sur l'inhibition de l'isoforme p110α de PI3K pour le traitement d'un cancer du poumon à petites cellules

Targeting the Phosphoinositide 3-Kinase p110α Isoform Impairs Cell Proliferation, Survival and Tumor Growth in Small Cell Lung Cancer

Wojtalla, Anna ; Fischer, Barbara ; Kotelevets, Nataliya ; Mauri, Francesco A. ; Sobek, Jens ; Rehrauer, Hubert ; Wotzkow, Carlos ; Tschan, Mario ; Seckl, Michael J. ; Zangemeister-Wittke, Uwe ; Arcaro, Alexandre

Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types. Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival [...]

Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, cette étude met en évidence un mécanisme par lequel, en activant la signalisation MEK-ERK, un inhibiteur sélectif de Cox-2, en particulier le célécoxib, induit une transition épithélio-mésenchymateuse

Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling

Wang, Zili ; Fan, Zhiqiang ; Jiang, Handong ; Qu, Jieming

Increasing evidence has suggested that high expression level of cyclooxygenase-2 (Cox-2) is associated with the malignancies of non-small cell lung cancer (NSCLC), leading to a rationale of applying Cox-2 inhibitors as adjuvant therapy in the treatment of NSCLC. However, the addition of celecoxib, a selective Cox-2 inhibitor, to chemotherapy in clinical trials failed to benefit the survival of NSCLC patients, which urges the investigation to re-evaluate this strategy for NSCLC treatment. In [...]

Menée sur des lignées cellulaires, cette étude suggère qu'un inhibiteur de MEK ou de IGF1R serait utile pour prévenir l'apparition de la mutation T790M du gène EGFR, liée à l'apparition d'une résistance au gefitinib ou à l'erlotinib dans le traitement d'un cancer du poumon non à petites cellules

Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors through a Multistep Mechanism Involving the IGF1R Pathway

Cortot, Alexis B ; Repellin, Claire E ; Shimamura, Takeshi ; Capelletti, Marzia ; Zejnullahu, Kreshnik ; Ercan, Dalia ; Christensen, James G. ; Wong, Kwok-Kin ; Gray, Nathanael S. ; Jänne, Pasi A

The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the [...]

Menée in vitro et sur trois modèles murins, cette étude met en évidence un mécanisme par lequel un composé appelé YR-20, en bloquant les voies de signalisation de TGFβ, inhibe le processus métastatique d'un cancer du sein

Inhibition of Breast Cancer Metastases by a Novel Inhibitor of TGFβ Receptor 1

Fang, Yuanzhang ; Chen, Yihua ; Yu, Linxi ; Zheng, Cong ; Qi, Ya ; Li, Zhenxi ; Yang, Zhengfeng ; Zhang, Yong ; Shi, Tieliu ; Luo, Jian ; Liu, Mingyao

Background Transforming growth factor beta (TGFβ), which is implicated in metastasis to various organs in breast cancer, is a potential target for new antitumor metastasis drugs .Methods To identify specific inhibitors of TGFβ receptor 1 (TGFβR1) in breast cancer metastasis, a virtual library of more than 400000 different compounds was screened by molecular docking modeling and confirmed with Smad-binding element luciferase and TGFβR1 kinase assays. Affymetrix GeneChip expression analysis of [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par les cellules NK dans la réponse à une virothérapie oncolytique pour le traitement d'un glioblastome

NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors

Alvarez-Breckenridge, Christopher A. ; Yu, Jianhua ; Price, Richard ; Wojton, Jeffrey ; Pradarelli, Jason ; Mao, Hsiaoyin ; Wei, Min ; Wang, Yan ; He, Shun ; Hardcastle, Jayson ; Fernandez, Soledad A. ; Kaur, Balveen ; Lawler, Sean E. ; Vivier, Eric ; Mandelboim, Ofer ; Moretta, Alessandro ; Caligiuri, Michael A. ; Chiocca, E. Antonio

The role of the immune response to oncolytic Herpes simplex viral (oHSV) therapy for glioblastoma is controversial because it might enhance or inhibit efficacy. We found that within hours of oHSV infection of glioblastomas in mice, activated natural killer (NK) cells are recruited to the site of infection. This response substantially diminished the efficacy of glioblastoma virotherapy. oHSV-activated NK cells coordinated macrophage and microglia activation within tumors. In vitro, human NK [...]

Mené sur 71 patients atteints d'une tumeur stromale gastro-intestinale de stade avancé, cet essai français de phase III évalue l'impact d'une interruption du traitement par imatinib sur la tumeur résiduelle, la qualité de la réponse thérapeutique et le délai d'apparition d'une résistance secondaire

Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial

Patrikidou, A. ; Chabaud, S. ; Ray-Coquard, I. ; Bui, B. N. ; Adenis, A. ; Rios, M. ; Bertucci, F. ; Duffaud, F. ; Chevreau, C. ; Cupissol, D. ; Domont, J. ; Pérol, D. ; Blay, J. Y. ; Le Cesne, A.

Background We previously demonstrated that interruption of imatinib mesylate (IM) in responding patients (pts) with advanced gastrointestinal stromal tumours (GISTs) results in rapid reprogression. The impact of interruption on residual tumour, quality of response and secondary resistance has not been fully investigated. Patients and methods Within the BRF14 study, 71 non-progressing patients were randomly assigned in the interruption arms after 1, 3 or 5 years. IM was resumed in the case of [...]

Menée sur 3 patients atteints d'un cancer réfractaire aux traitements conventionnels (côlon-rectum, rein, mélanome), cette étude présente les résultats à long terme (3 ans) d'une immunothérapie à base d'un composé appelé BMS-936558, un anticorps anti-PD-1

Durable Cancer Regression Off-treatment and Effective Re-induction Therapy with an Anti-PD-1 Antibody

Lipson, Evan J ; Sharfman, William H ; Drake, Charles G. ; Wollner, Ira ; Taube, Janis M ; Anders, Robert A. ; Xu, Haiying ; Yao, Sheng ; Pons, Alice ; Chen, Lieping ; Pardoll, Drew M ; Brahmer, Julie R ; Topalian, Suzanne L

Purpose Results from the first-in-human phase I trial of the anti-programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that re-induction therapy for late tumor recurrence can be effective. [...]

A partir d'une revue systématique de la littérature (32 études), cette méta-analyse évalue les gains de survie liés à divers protocoles de chimiothérapie à base de sels de platine ou de taxanes chez les patients atteints d'un cancer d'origine primitive inconnue

Evaluation of survival benefits by platinums and taxanes for an unfavourable subset of carcinoma of unknown primary: a systematic review and meta-analysis

Lee, J. ; Hahn, S. ; Kim, D. W. ; Kim, J. ; Kang, S. N. ; Rha, S. Y. ; Lee, K. B. ; Kang, J. H. ; Park, B. J.

Background : Although chemotherapeutic regimens containing a taxane or platinum agent have been widely recommended for unfavourable carcinoma of unknown primary (CUP), no evidence exists for the superiority of any administered regimens. To date, the efficacy has been mostly assessed in the limited setting of phase II trials, and few attempts have been made to synthesise all available data for survival outcomes. Methods: Electronic databases were searched from 1980 to 2011. Survival results were [...]

Mené sur 65 patients adultes atteints d'une leucémie aiguë lymphoblastique Ph- récidivante, cet essai international de phase II évalue, du point de vue de la rémission complète, des hautes doses de liposomes de sulfate de vincristine en injection intraveineuse

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

O’Brien, Susan ; Schiller, Gary ; Lister, John ; Damon, Lloyd ; Goldberg, Stuart ; Aulitzky, Walter ; Ben-Yehuda, Dina ; Stock, Wendy ; Coutre, Steven ; Douer, Dan ; Heffner, Leonard T. ; Larson, Melissa ; Seiter, Karen ; Smith, Scott ; Assouline, Sarit ; Kuriakose, Philip ; Maness, Lori ; Nagler, Arnon ; Rowe, Jacob ; Schaich, Markus ; Shpilberg, Ofer ; Yee, Karen ; Schmieder, Guenter ; Silverman, Jeffrey A. ; Thomas, Deborah ; Deitcher, Steven R. ; Kantarjian, Hagop

Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, [...]

A partir de données portant sur 2 962 patients adultes atteints d'une leucémie aiguë lymphoblastique non Ph+ et inclus dans 13 essais cliniques, cette méta-analyse montre qu'une greffe allogénique de cellules hématopoïétiques, et non une greffe autologue, améliore la survie globale des patients de moins de 35 ans

Allogeneic, but not autologous, hematopoietic-cell-transplant improves survival only among younger adults with acute lymphoblastic leukemia in first remission: individual-patient-data meta-analysis

Gupta, Vikas ; Richards, Sue ; Rowe, Jacob

Haematopoietic cell transplant (HCT) and prolonged chemotherapy are standard post remission strategies for adult acute lymphoblastic leukaemia (ALL) in first complete remission (CR1), but optimal strategy remains controversial. There are no randomised trials of allogeneic HCT. Updated individual patient data were collected and analysed from studies with information on availability of matched sibling donor (used to mimic randomisation) and from randomised trials of autograft versus chemotherapy. [...]

Cet article compare les travaux récents sur l'efficacité et la toxicité du bortezomib, du thalidomide et du lénalidomide pour le traitement de patients atteints d'un myélome multiple à haut risque

Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma

Bergsagel, P. Leif ; Mateos, María-Victoria ; Gutiérrez, Norma C. ; Rajkumar, S. Vincent ; San Miguel, Jesús F.

Multiple myeloma (MM) is a heterogeneous disease with certain genetic features (e.g., t(4;14), del17p) associated with worse outcome. The introduction of thalidomide, lenalidomide and bortezomib has dramatically improved the outlook for patients with MM, but their relative benefit (or harm) for different genetic patient subgroups remains unclear. Unfortunately, the small numbers of patients in each subgroup frequently limits the analysis of high-risk patients enrolled in clinical trials. [...]

Cet article passe en revue les travaux récents sur le bevacizumab pour le traitement d'un cancer ovarien

Bevacizumab and ovarian cancer

Garcia, Agustin ; Singh, Harpreet

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor-A, and is indicated in the treatment of various tumors (colon, lung, renal, and glioblastoma). It has been recently approved for the treatment of ovarian cancer in various countries. This review summarizes the activity and toxicity of bevacizumab in the treatment of ovarian cancer, both as single-agent drug and in combination with cytotoxic chemotherapy. As a single-agent drug, it has [...]

A partir d'une revue de la littérature sur des essais randomisés ayant évalué l'ajout de bevacizumab à une chimiothérapie à base de sels de platine pour le traitement d'un cancer non à petites cellules récidivant ou métastatique (total de 2 194 patients), cette méta-analyse évalue l'impact du bevacizumab sur la survie globale et la survie sans progression

Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer

Soria, J.-C. ; Mauguen, A. ; Reck, M. ; Sandler, A. B. ; Saijo, N. ; Johnson, D. H. ; Burcoveanu, D. ; Fukuoka, M. ; Besse, B. ; Pignon, J.-P.

Background Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC). Methods Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were [...]

Mené sur 171 patients atteints d'un cancer de la prostate résistant à la castration, cet essai de phase II évalue le cabozantinib, du point de vue du taux de réponse objective à 12 semaines et de la survie sans progression

Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial

Smith, David C. ; Smith, Matthew R. ; Sweeney, Christopher ; Elfiky, Aymen A. ; Logothetis, Christopher ; Corn, Paul G. ; Vogelzang, Nicholas J. ; Small, Eric J. ; Harzstark, Andrea L. ; Gordon, Michael S. ; Vaishampayan, Ulka N. ; Haas, Naomi B. ; Spira, Alexander I. ; Lara, Primo N. ; Lin, Chia-Chi ; Srinivas, Sandy ; Sella, Avishay ; Schöffski, Patrick ; Scheffold, Christian ; Weitzman, Aaron L. ; Hussain, Maha

Purpose Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients and Methods Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or [...]

Mené sur 54 patients atteints d'un carcinome métastatique du rhinopharynx, cet essai chinois de phase II évalue l'efficacité et la toxicité du sorafenib en traitement d'entretien après une chimiothérapie à base de cisplatine et 5-fluorouracile

Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma

Xue, C. ; Huang, Y. ; Huang, P. Y. ; Yu, Q. T. ; Pan, J. J. ; Liu, L. Z. ; Song, X. Q. ; Lin, S. J. ; Wu, J. X. ; Zhang, J. W. ; Zhao, H. Y. ; Xu, F. ; Liu, J. L. ; Hu, Z. H. ; Zhao, L. P. ; Zhao, Y. Y. ; Wu, X. ; Zhang, J. ; Ma, Y. X. ; Zhang, L.

Background We aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC). Patients and methods It was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m2 i.v. day 1, and 5-FU 1000 mg/m2/day CIV for 4 days, repeated every 21 days. After a [...]

Menée in vitro et à l'aide d'une xénogreffe de tumeur humaine, cette étude montre qu'un anticorps monoclonal ciblant les récepteurs EGFR et HER3 peut inhiber la résistance des cellules tumorales aux rayonnements ionisants et aux inhibiteurs du récepteur EGFR

Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation

Huang, Shyh-Min ; Li, Chunrong ; Armstrong, Eric A ; Peet, Chimera R ; Saker, Jarob ; Amler, Lukas C. ; Sliwkowski, Mark X. ; Harari, Paul

EGFR inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell cycle progression in parallel with EGFR/HER3 signaling [...]

Cet article passe en revue les études récentes sur les traitements utilisant un agent chimique perturbant la vascularisation tumorale en combinaison avec des rayonnements ionisants

Combination of vascular disrupting agents and ionizing radiation

Clémenson, Céline ; Chargari, Cyrus ; Deutsch, Eric

Vascular disrupting agents (VDAs) are a relatively new class of drugs that target tumor vasculature and induce tumor blood flow shutdown and subsequent necrosis in the tumor core. The first generation of these agents is actively evaluated in clinical trials, whereas new molecules are developed in order to enhance efficacy and to overcome resistance mechanisms. VDA used as a single agent only cause a moderate tumor growth delay. So, strategy aiming at combining VDA to conventional cancer [...]

Cet article met à jour les données concernant un essai de phase II évaluant, du point de vue de la survie globale à 5 ans, l'efficacité et la toxicité à long terme d'une radiothérapie combinée au nédaplatine et au 5-fluorouracile chez des patients atteints d'un cancer de l'œsophage avec récidive loco-régionale après une intervention chirurgicale (30 cas)

Long-term results of radiotherapy combined with nedaplatin and 5-fluorouracil for postoperative loco-regional recurrent esophageal cancer: update on a phase II study

Jingu, Keiichi ; Matsushita, Haruo ; Takeda, Ken ; Umezawa, Rei ; Takahashi, Chiaki ; Sugawara, Toshiyuki ; Kubozono, Masaki ; Abe, Keiko ; Tanabe, Takaya ; Shirata, Yuko ; Yamamoto, Takaya ; Ishikawa, Youjirou ; Nemoto, Kenji

BACKGROUND:In 2006, we reported the effectiveness of chemoradiotherapy for postoperative recurrent esophageal cancer with a median observation period of 18 months. The purpose of the present study was to update the results of radiotherapy combined with nedaplatin and 5-fluorouracil (5-FU) for postoperative loco-regional recurrent esophageal cancer.METHODS:Between 2000 and 2004, we performed a phase II study on treatment of postoperative loco-regional recurrent esophageal cancer with [...]

Menée sur un modèle murin de cancer de la prostate, cette étude montre que des macrophages délivrant une grande quantité de virus oncolytiques peuvent inhiber la croissance tumorale et la formation de métastases après une chimiothérapie par docétaxel ou une radiothérapie

Macrophage Delivery of an Oncolytic Virus Abolishes Tumor Regrowth and Metastasis After Chemotherapy or Irradiation

Muthana, Munitta ; Rodrigues, Samuel ; Chen, Yung-Yi ; Welford, Abigail ; Hughes, Russell ; Tazzyman, Simon ; Essand, Magnus ; Morrow, Fiona ; Lewis, Claire E

Frontline anti-cancer therapies like chemotherapy and irradiation often slow tumor growth but tumor regrowth and spread to distant sites usually occurs after the conclusion of treatment. We recently demonstrated that macrophages could be used to deliver large quantities of a hypoxia-regulated, prostate-specific oncolytic (OV) virus to prostate tumours. In the current study we show that administration of such OV-armed macrophages 48 hours after chemotherapy (docetaxel) or tumor irradiation [...]

Menés respectivement sur 31 et 147 patients atteints d'un glioblastome diagnostiqué entre 2002 et 2004, cet essai de phase I/II évalue, du point de vue de la survie globale et des événements indésirables, l'intérêt d'ajouter à une radiothérapie un traitement concomitant par gefitinib

RTOG 0211: A Phase 1/2 Study of Radiation Therapy With Concurrent Gefitinib for Newly Diagnosed Glioblastoma Patients

Chakravarti, Arnab ; Wang, Meihua ; Robins, H. Ian ; Lautenschlaeger, Tim ; Curran, Walter J. ; Brachman, David G. ; Schultz, Christopher J. ; Choucair, Ali ; Dolled-Filhart, Marisa ; Christiansen, Jason ; Gustavson, Mark ; Molinaro, Annette ; Mischel, Paul ; Dicker, Adam P. ; Bredel, Markus ; Mehta, Minesh

To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients. Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for [...]

Mené sur 15 patients atteints d'un carcinome épidermoïde cutané de la tête et du cou de stade avancé, cet essai de phase I évalue, du point de vue de la survie globale à 2 ans et des événements indésirables, l'efficacité et la toxicité d'un traitement combinant erlotinib et radiothérapie

Phase 1 Study of Erlotinib Plus Radiation Therapy in Patients With Advanced Cutaneous Squamous Cell Carcinoma

Heath, C. Hope ; Deep, Nicholas L. ; Nabell, Lisle ; Carroll, William R. ; Desmond, Renee ; Clemons, Lisa ; Spencer, Sharon ; Magnuson, J. Scott ; Rosenthal, Eben L.

To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma. This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method. The majority of patients were male (87%) and presented with T4 [...]

Menée sur 520 patients atteints d'un carcinome épidermoïde glottique ou sus-glottique de stade III ou IV (durée médiane de suivi : 10,8 ans), cette étude compare, du point de vue de la survie sans laryngectomie, l'efficacité de trois stratégies thérapeutiques préservant le larynx : une chimiothérapie d'induction par cisplatine-fluorouracile suivie par une radiothérapie, une chimioradiothérapie concomitante par cisplatine et une radiothérapie seule

Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer

Forastiere, Arlene A. ; Zhang, Qiang ; Weber, Randal S. ; Maor, Moshe H. ; Goepfert, Helmuth ; Pajak, Thomas F. ; Morrison, William ; Glisson, Bonnie ; Trotti, Andy ; Ridge, John A. ; Thorstad, Wade ; Wagner, Henry ; Ensley, John F. ; Cooper, Jay S.

Purpose To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation.Patients and Methods Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the [...]

Menée par questionnaire auprès de 683 participants (auteurs d'essais cliniques publiés en 2010 ou 2011), cette étude évalue leurs opinions et leurs expériences en matière de partage des données

Sharing of clinical trial data among trialists: a cross sectional survey

Vinay Rathi ; Kristina Dzara ; Cary P Gross ; Iain Hrynaszkiewicz ; Steven Joffe ; Harlan M Krumholz ; Kelly M Strait ; Joseph S Ross

Objective To investigate clinical trialists’ opinions and experiences of sharing of clinical trial data with investigators who are not directly collaborating with the research team. Design and setting Cross sectional, web based survey. Participants Clinical trialists who were corresponding authors of clinical trials published in 2010 or 2011 in one of six general medical journals with the highest impact factor in 2011. Main outcome measures Support for and prevalence of data sharing through [...]

Cette étude compare l'intérêt de deux critères de jugement d'un essai de phase II, la survie sans progression et l'évolution de la tumeur à partir de la somme de ses plus grands diamètres, pour décider de l'opportunité d'entreprendre un essai de phase III

Tumor Burden Modeling versus Progression-Free Survival for Phase II Decision Making

Kaiser, Lee D

Randomized Phase II oncology trial endpoints for decision making include both progression-free survival (PFS) and change in tumor burden as measured by the sum of longest diameters (SLD) of the target lesions. In addition to observed SLD changes, tumor shrinkage and growth parameters can be estimated from the patient-specific SLD profile over time. The ability of these SLD analyses to identify an active drug is contrasted with that of a PFS analysis through the simulation of Phase II trials via [...]

A partir de données portant sur 1 908 patients inclus dans 55 essais cliniques de phase I ayant porté sur une thérapie ciblée entre 2000 et 2009, cette étude analyse l'intérêt, du point de vue des bénéfices apportés aux patients, de chercher à déterminer une dose maximale tolérée pour évaluer une thérapie ciblée

Meta-analysis of the Relationship Between Dose and Benefit in Phase I Targeted Agent Trials

Gupta, Sachin ; Hunsberger, Sally ; Boerner, Scott A. ; Rubinstein, Larry ; Royds, Robert ; Ivy, Percy ; LoRusso, Patricia

Background To date, the primary objective of phase I trials has been to safely select the maximum tolerated dose (MTD) of a drug or drug combination for utilization in subsequent trials. Although conventional cytotoxic chemotherapy is generally more effective at the MTD than molecularly targeted agents (MTAs), recent single-institution data suggest that molecularly targeted agent may not require an MTD for efficacy. We analyzed patient outcome results in MTA phase I trials at multiple [...]