Cet article fait le point sur l'utilisation de la chirurgie dans le traitement d'un cancer de la prostate à haut risque de récidive.

The status of surgery in the management of high-risk prostate cancer

Christian Bach, Sailaja Pisipati, Datesh Daneshwar, Mark Wright, Edward Rowe, David Gillatt, Raj Persad & Anthony Koupparis

Radiation therapy combined with androgen-deprivation therapy has become the standard-of-care treatment for patients with high-risk prostate cancer; however, superiority of this approach over other therapeutic options, such as surgery, has not been clearly demonstrated. This Review provides a comprehensive overview of the current status of surgery in the treatment of high-risk prostate cancer and highlights the findings that might underlie the increasing use of radical prostatectomy as the [...]

Cet article passe en revue les travaux récents sur les inhibiteurs de MEK pour le traitement de divers types de cancer

The clinical development of MEK inhibitors

Zhao, Yujie ; Adjei, Alex A.

Aberrant activation of the RAS-RAF-MEK-ERK1/2 pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis and, therefore, MEK1/2 inhibition is an attractive therapeutic strategy in a number of cancers. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed and assessed in numerous clinical studies over the past decade. These agents are not [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'une stratégie combinant le cetuximab et un anticorps monoclonal anti CD137 pour le traitement d'un cancer exprimant EGFR

Targeting CD137 enhances the efficacy of cetuximab

Kohrt, Holbrook E. ; Colevas, A. Dimitrios ; Houot, Roch ; Weiskopf, Kipp ; Goldstein, Matthew J. ; Lund, Peder ; Mueller, Antonia ; Sagiv-Barfi, Idit ; Marabelle, Aurelien ; Lira, Ruth ; Troutner, Emily ; Richards, Lori ; Rajapaska, Amanda ; Hebb, Jonathan ; Chester, Cariad ; Waller, Erin ; Ostashko, Anton ; Weng, Wen-Kai ; Chen, Lieping ; Czerwinski, Debra ; Fu, Yang-Xin ; Sunwoo, John ; Levy, Ronald

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'un traitement combinant l'olaparib, un inhibiteur de PARP, et un composé appelé AZD7762, un inhibiteur de ChK1, pour le traitement d'un cancer de la prostate résistant à la castration

Targeting Poly(ADP-Ribose) Polymerase and the c-Myb-Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer

Li, Likun ; Chang, Wenjun ; Yang, Guang ; Ren, Chengzhen ; Park, Sanghee ; Karantanos, Theodoros ; Karanika, Styliani ; Wang, Jianxiang ; Yin, Jianhua ; Shah, Parantu K. ; Takahiro, Hirayama ; Dobashi, Masato ; Zhang, Wenling ; Efstathiou, Eleni ; Maity, Sankar N. ; Aparicio, Ana M. ; Li Ning Tapia, Elsa M. ; Troncoso, Patricia ; Broom, Bradley ; Xiao, Lianchun ; Lee, Hyun-Sung ; Lee, Ju-Seog ; Corn, Paul G. ; Navone, Nora ; Thompson, Timothy C.

Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that [...]

Cet article passe en revue le développement de nouveaux agents cibant la signalisation du récepteur aux androgènes pour le traitement des patients atteints d'un cancer de la prostate résistant à la castration

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

Ferraldeschi, R. ; Welti, J. ; Luo, J. ; Attard, G. ; de Bono, J. S.

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and [...]

Cet article analyse les perspectives offertes par le nintedanib pour le traitement des patients atteints d'un cancer colorectal métastatique

What Could Nintedanib (BIBF 1120), a Triple Inhibitor of VEGFR, PDGFR, and FGFR, Add to the Current Treatment Options for Patients with Metastatic Colorectal Cancer?

Capdevila, Jaume ; Carrato, Alfredo ; Tabernero, Josep ; Grande, Enrique

Increasing knowledge of the pro-angiogenic processes involved in the progression of metastatic colorectal cancer (mCRC) has resulted in the clinical development of several anti-angiogenic agents, with bevacizumab currently being the only approved agent for mCRC. Nintedanib (BIBF 1120) has been shown to block the vascular endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor (PDGFR), and the fibroblast growth factor receptor (FGFR). By targeting FGFR signaling, [...]

Cet article passe en revue les travaux récents sur les neuropathies périphériques induites par une chimiothérapie

Chemotherapy-induced neuropathy: A comprehensive survey

Miltenburg, N. C. ; Boogerd, W.

Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide. Supposed pathogenetic mechanisms of CIPN are axonopathy through dying back axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The exact pathophysiology however is not clear and different underlying mechanisms have been proposed for different [...]

Mené sur 381 patients atteints d'une leucémie myéloïde aiguë récidivante/réfractaire, cet essai multicentrique international de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'elacytarabine

International Randomized Phase III Study of Elacytarabine Versus Investigator Choice in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Roboz, Gail J. ; Rosenblat, Todd ; Arellano, Martha ; Gobbi, Marco ; Altman, Jessica K. ; Montesinos, Pau ; O’Connell, Casey ; Solomon, Scott R. ; Pigneux, Arnaud ; Vey, Norbert ; Hills, Robert ; Jacobsen, Tove Flem ; Gianella-Borradori, Athos ; Foss, Øivind ; Vetrhusand, Sylvia ; Giles, Francis J.

Purpose : Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator’s choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent [...]

Mené sur 106 patients atteints d'un myélome multiple récemment diagnostiqué, cet essai de phase II évalue l'efficacité et la toxité de l'ajout de siltuximab, un anticorps monoclonal anti IL-6, à un traitement combinant bortezomib, melphalan et prednisone

Randomized, open label, phase 2 study of siltuximab (an anti IL 6 mAb) and bortezomib melphalan prednisone versus bortezomib-melphalan-prednisone in patients with newly diagnosed multiple myeloma

San Miguel, Jesús ; Bladé, Joan ; Shpilberg, Ofer ; Grosicki, Sebastian ; Maloisel, Frédéric ; Min, Chang-Ki ; Polo Zarzuela, Marta ; Robak, Tadeusz ; Prasad, Sripada V.S.S. ; Goh, Yeow Tee ; Laubach, Jacob ; Spencer, Andrew ; Mateos, María-Victoria ; Palumbo, Antonio ; Puchalski, Tom ; Reddy, Manjula ; Uhlar, Clarissa ; Qin, Xiang ; van de Velde, Helgi ; Xie, Hong ; Orlowski, Robert Z.

As interleukin (IL)-6 is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab (S) to the VMP (bortezomib-melphalan-prednisone) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP+siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics [...]

Mené sur 301 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'erlotinib et du docétaxel en traitement de deuxième ou troisième ligne

Randomized Phase III Trial of Erlotinib Versus Docetaxel As Second- or Third-Line Therapy in Patients With Advanced Non–Small-Cell Lung Cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA)

Kawaguchi, Tomoya ; Ando, Masahiko ; Asami, Kazuhiro ; Okano, Yoshio ; Fukuda, Masaaki ; Nakagawa, Hideyuki ; Ibata, Hidenori ; Kozuki, Toshiyuki ; Endo, Takeo ; Tamura, Atsuhisa ; Kamimura, Mitsuhiro ; Sakamoto, Kazuhiro ; Yoshimi, Michihiro ; Soejima, Yoshifumi ; Tomizawa, Yoshio ; Isa, Shun-ichi ; Takada, Minoru ; Saka, Hideo ; Kubo, Akihito

Purpose : To investigate the efficacy of erlotinib versus docetaxel in previously treated patients with advanced non–small-cell lung cancer (NSCLC) in an epidermal growth factor receptor (EGFR) –unselected patient population. Patients and Methods : The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate, safety, and analyses on EGFR wild-type tumors. Patients with stage IIIB or IV NSCLC, previous treatment with one or two [...]

Cet article passe en revue l'évolution des traitements ciblant le récepteur aux androgènes pour les patients atteints d'un cancer avancé de la prostate

Evolution of androgen receptor targeted therapy for advanced prostate cancer

Wong, Yien Ning Sophia ; Ferraldeschi, Roberta ; Attard, Gerhardt ; de Bono, Johann

The discovery of androgen dependence in prostate cancer in 1941 by Huggins and colleagues has remained the backbone for the treatment of this disease. However, although many patients initially respond to androgen depletion therapy, they almost invariably relapse and develop resistance with transition of the disease to a castration-resistant state. Over the past decade, the better understanding of the mechanisms that drive resistance to castration has led to the development of next-generation [...]

Cet article passe en revue les travaux récents sur la prise en charge et le traitement des patients atteints d'un cancer de la prostate à haut risque

High-risk prostate cancer - classification and therapy

Chang, Albert J. ; Autio, Karen A. ; Roach Iii, Mack ; Scher, Howard I.

Approximately 15% of patients with prostate cancer are diagnosed with high-risk disease. However, the current definitions of high-risk prostate cancer include a heterogeneous group of patients with a range of prognoses. Some have the potential to progress to a lethal phenotype that can be fatal, while others can be cured with treatment of the primary tumour alone. The optimal management of this patient subgroup is evolving. A refined classification scheme is needed to enable the early and [...]

Mené sur 60 patientes atteintes d'un cancer du sein triplement négatif opérable, cet essai de phase II évalue l'efficacité, du point de vue de la réponse pathologique complète, et la toxicité du panitumumab en combinaison avec une chimiothérapie à base d'anthracycline et de taxane pour un traitement néoadjuvant, puis identifie divers biomarqueurs associés à la réponse thérapeutique

Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane based chemotherapy in operable triple negative breast cancer: Identification of biologically-defined signatures predicting treatment impact

Nabholtz, J.M. ; Abrial, C. ; Mouret-Reynier, M.A. ; Dauplat, M.M. ; Weber, B. ; Gligorov, J. ; Forest, A.M. ; Tredan, O. ; Vanlemmens, L. ; Petit, T. ; Guiu, S. ; Van Praagh, I. ; Jouannaud, C. ; Dubray-Longeras, P. ; Tubiana-Mathieu, N. ; Benmammar, K.E. ; Kullab, S. ; Bahadoor, M.R.K. ; Radosevic-Robin, N. ; Kwiatkowski, F. ; Desrichard, A. ; Cayre, A. ; Uhrhammer, N. ; Chalabi, N. ; Chollet, P. ; Penault-Llorca, F.

Background : Triple negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the Epithelial Growth Factor Receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline-taxane based chemotherapy in patients with operable, stage II-III, TNBC. Methods : Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for 8 [...]

Mené sur 940 patients atteints d'un carcinome épidermoïde de l'anus (durée médiane de suivi : 5,1 ans ), cet essai évalue l'effet d'un traitement, combinant ou non une chimioradiothérapie par 5-fluorouracile-cisplatine ou 5-fluorouracile-mitomycine et une chimiothérapie d'entretien, sur la survie sans progression et la survie sans colostomie, puis identifie les facteurs prédictifs associés à la survie sans colostomie

Tumour- and treatment-related colostomy rates following Mitomycin or Cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial

Glynne-Jones, R. ; Kadalayil, L. ; Meadows, H.M. ; Cunningham, D. ; Samuel, L. ; Geh, J.I. ; Lowdell, C. ; James, R. ; Beare, S. ; Begum, R. ; Ledermann, J.A. ; Sebag-Montefiore, D. ; on behalf of the ACT II study group

Background : Squamous cell carcinoma of the anus (SCCA) is highly sensitive to chemoradiation which achieves good loco-regional control and preserves anal function. However some patients require permanent stoma formation either as a result of surgery on relapse, poor anal function or treatment-related symptoms. Our aim was to determine patient, tumor and treatment-related colostomy rates following chemoradiation (CRT) and maintenance chemotherapy in the ACT II trial. Patients and methods : The [...]

Menée à partir de questionnaires auprès de 56 centres de transfusion sanguine et de greffe de moelle osseuse, cette étude européenne met en évidence l'extrême hétérogénéité des techniques d'irradiation corporelle totale myéloablative avant une greffe de cellules souches hématopoïétiques

Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: A survey of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Giebel, Sebastian ; Miszczyk, Leszek ; Slosarek, Krzysztof ; Moukhtari, Leila ; Ciceri, Fabio ; Esteve, Jordi ; Gorin, Norbert-Claude ; Labopin, Myriam ; Nagler, Arnon ; Schmid, Christoph ; Mohty, Mohamad

BACKGROUND : Total body irradiation (TBI) is widely used for conditioning before hematopoietic cell transplantation. Its efficacy and toxicity may depend on many methodological aspects. The goal of the current study was to explore current clinical practice in this field. METHODS : A questionnaire was sent to all centers collaborating in the European Group for Blood and Marrow Transplantation and included 19 questions regarding various aspects of TBI. A total of 56 centers from 23 countries [...]

Mené sur 50 patients atteints d'un sarcome des tissus mous des extrémités avec risque élevé de récidive (durée médiane de suivi : 48 mois), cet essai prospectif de phase II évalue l'efficacité, du point de vue du contrôle local et de la survie globale, et la toxicité d'un traitement multimodal incluant une radiothérapie intra-opératoire par faisceaux d'électrons et une radiothérapie externe post-opératoire

Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial

Roeder, Falk ; Lehner, Burkhard ; Schmitt, Thomas ; Kasper, Bernd ; Egerer, Gerlinde ; Sedlaczek, Oliver ; Grullich, Carsten ; Mechtersheimer, Gunhild ; Wuchter, Patrick ; Hensley, Frank ; Huber, Peter ; Debus, Juergen ; Bischof, Marc

Background : To report the results of a subgroup analysis of a prospective phase II trial focussing on radiation therapy and outcome in patients with extremity soft tissue sarcomas (STS). Methods : Between 2005 and 2010, 50 patients (pts) with high risk STS (size >= 5 cm, deep/extracompartimental location, grade II-III (FNCLCC)) were enrolled. The protocol comprised 4 cycles of neoadjuvant chemotherapy with EIA (etoposide, ifosfamide and doxorubicin), definitive surgery with IOERT, [...]