Mené sur 22 patients atteints d'un mélanome de stade IV, cet essai évalue la tolérabilité d'un traitement combinant radiothérapie et ipilimumab

A Prospective Clinical Trial Combining Radiation Therapy with Systemic Immunotherapy in Metastatic Melanoma

Hiniker, Susan M. ; Reddy, Sunil A. ; Maecker, Holden T. ; Subrahmanyam, Priyanka B. ; Rosenberg-Hasson, Yael ; Swetter, Susan M. ; Saha, Saurabh ; Shura, Lei ; Knox, Susan J.

Purpose : Local radiation therapy (RT) in combination with systemic anti-CTLA-4 immunotherapy may enhance induction of systemic anti-melanoma immune responses. The primary objective of this trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. Secondary objectives included laboratory assessment of induction of anti-melanoma immune responses. Materials/Methods : In our prospective clinical trial, 22 patients with stage IV melanoma were [...]

Menée sur 345 patientes atteintes d'un cancer du sein traité par mastectomie et ayant subi un curage ganglionnaire axillaire après une biopsie du ganglion sentinelle dont le résultat s'est avéré positif, cette étude évalue la proportion de patientes ayant reçu une radiothérapie après le curage ganglionnaire, puis évalue le risque de récidive loco-régionale en fonction du traitement reçu (radiothérapie ou non) et de la présence d'une atteinte ganglionnaire axillaire

Use of post-mastectomy radiotherapy in patients receiving completion axillary lymph node dissection after a positive sentinel lymph node biopsy

Stauder, Michael C. ; Caudle, Abigail S. ; Allen, Pamela K. ; Shaitelman, Simona F. ; Smith, Benjamin D. ; Hoffman, Karen E. ; Buchholz, Thomas A. ; Chavez-MacGregor, Mariana ; Hunt, Kelly K. ; Meric-Bernstam, Funda ; Woodward, Wendy A.

Purpose : We sought to determine the rate of PMRT among women treated with ALND after a positive SLN biopsy and to establish the effect of a negative ALND and PMRT on local-regional recurrence (LRR) and overall survival (OS). Methods : All patients were treated with mastectomy and ALND after a positive SLN biopsy. All patients were clinical N0 or Nx at the time of mastectomy and received no neoadjuvant therapy. The presence of LVSI, multifocality, number of positive SLN and non-sentinel lymph [...]

Menée sur 134 patientes atteintes d'un cancer invasif du sein de stade T1–2N0–1, cette étude évalue, du point de vue de la réduction du volume tissulaire réséqué et de la qualité des marges de résection, l'intérêt d'un traitement chirurgical conservateur guidé par échographie

Ultrasound-guided breast-conserving surgery for early-stage palpable and nonpalpable invasive breast cancer: decreased excision volume at unchanged tumor-free resection margin

Slijkhuis, W. A. ; Noorda, E. M. ; van der Zaag-Loonen, H. ; Eenennaam, M. J. Bolster-van ; Greve, K. E. Droogh-de ; Lastdrager, W. B. ; Gratama, J. W. C.

Ultrasound guidance (USG) during breast-conserving surgery improves tumor-free surgical resection margins. The objective of this study was to evaluate whether USG reduces resection volumes without compromising margin status. 134 patients with palpable or nonpalpable T1–2N0–1 invasive breast cancer were treated with USG and compared with a historical reference control group (CON) consisting of palpation-guided (PAG) or wire-guided localization (WIG) breast-conserving surgery. Primary outcomes [...]

A partir d'une analyse d'échantillons tumoraux prélevés sur 85 patients atteints d'une tumeur stromale gastro-intestinale, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant l'intérêt d'immunothérapies anti PD1/PD-L1 pour renforcer l'efficacité de l'imatinib

PD-1/PD-L1 blockade enhances T cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors

Seifert, Adrian M. ; Zeng, Shan ; Zhang, Jennifer Q. ; Kim, Teresa S. ; Cohen, Noah A. ; Beckman, Michael J. ; Medina, Benjamin D. ; Maltbaek, Joanna H. ; Loo, Jennifer K. ; Crawley, Megan H. ; Rossi, Ferdinand ; Besmer, Peter ; Antonescu, Cristina R. ; DeMatteo, Ronald P.

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumor (GIST), but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GIST. Experimental Design: We analyzed tumor and matched blood samples from 85 patients [...]

Menée in vivo sur des modèles de divers types de cancer, cette étude évalue l'activité antitumorale de nanoparticules lipidiques acheminant dans les tumeurs des ARNs interférents ciblant le gène codant la bêta-caténine

Direct pharmacological inhibition of beta-catenin by RNA interference in tumors of diverse origin

Ganesh, Shanthi ; Koser, Martin ; Cyr, Wendy ; Chopda, Girish ; Tao, Junyan ; Shui, Xue ; Ying, Bo ; Chen, Dongyu ; Pandya, Purva ; Chipumuro, Edmond ; Siddiquee, Zakir ; Craig, Kevin ; Lai, Chengjung ; Dudek, Henryk ; Monga, Satdarshan ; Wang, Weimin ; Brown, Bob D. ; Abrams, Marc

The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level, and therefore can be applied to previously-undruggable targets. Lipid nanoparticles (LNPs) represent an elegant solution for delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have [...]

Menée sur des lignées cellulaires cancéreuses résistantes au cétuximab, puis à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'une thérapie appelée Pan-HER, composée de six anticorps ciblant des récepteurs de la famille HER

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

Iida, Mari ; Bahrar, Harsh ; Brand, Toni M. ; Pearson, Hannah E. ; Coan, John P. ; Orbuch, Rachel A. ; Flanigan, Bailey G. ; Swick, Adam D. ; Prabakaran, Prashanth ; Lantto, Johan ; Horak, Ivan D. ; Kragh, Michael ; Salgia, Ravi ; Kimple, Randall J. ; Wheeler, Deric L.

Cetuximab, an antibody against the Epidermal Growth Factor Receptor (EGFR) has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To [...]

Cet article passe en revue les travaux récents sur le développement de traitements anticancéreux à base de virus oncolytiques

Oncolytic viruses in cancer treatment: A review

Lawler, S. E. ; Speranza, M. ; Cho, C. ; Chiocca, E.

Importance  Oncolytic viruses (OVs) are emerging as important agents in cancer treatment. Oncolytic viruses offer the attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, therefore acting as potential in situ tumor vaccines. Moreover, OVs can be engineered for optimization of tumor selectivity and enhanced immune stimulation and can be readily combined with other agents. The effectiveness of OVs has been demonstrated in many preclinical studies and [...]

Cet article passe en revue les travaux récents sur les mécanismes impliquant autophagie, inflammation et immunité dans le développement d'une tumeur maligne et dans la réponse aux immunothérapies

Autophagy, Inflammation, and Immunity: A Troika Governing Cancer and Its Treatment

Zhong, Zhenyu ; Sanchez-Lopez, Elsa ; Karin, Michael

Autophagy, a cellular waste disposal process, has well-established tumor-suppressive properties. New studies indicate that, in addition to its cell-autonomous anti-tumorigenic functions, autophagy inhibits cancer development by orchestrating inflammation and immunity. While attenuating tumor-promoting inflammation, autophagy enhances the processing and presentation of tumor antigens and thereby stimulates anti-tumor immunity. Although cancer cells can escape immunosurveillance by tuning down [...]

A partir d'échantillons tumoraux prélevés sur 4 patients atteints d'un mélanome métastatique ayant progressé après une phase de réponse au pembrolizumab, cette étude identifie un ensemble de mutations associées à la résistance thérapeutique

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Zaretsky, Jesse M. ; Garcia-Diaz, Angel ; Shin, Daniel S. ; Escuin-Ordinas, Helena ; Hugo, Willy ; Hu-Lieskovan, Siwen ; Torrejon, Davis Y. ; Abril-Rodriguez, Gabriel ; Sandoval, Salemiz ; Barthly, Lucas ; Saco, Justin ; Homet Moreno, Blanca ; Mezzadra, Riccardo ; Chmielowski, Bartosz ; Ruchalski, Kathleen ; Shintaku, I. Peter ; Sanchez, Phillip J. ; Puig-Saus, Cristina ; Cherry, Grace ; Seja, Elizabeth ; Kong, Xiangju ; Pang, Jia ; Berent-Maoz, Beata ; Comin-Anduix, Begona ; Graeber, Thomas G. ; Tumeh, Paul C. ; Schumacher, Ton N.M. ; Lo, Roger S. ; Ribas, Antoni

BACKGROUND : Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS : We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in [...]

Menée à l'aide d'un modèle murin de mésothéliome, cette étude met en évidence des mécanismes suggérant l'intérêt d'une immunothérapie anti PD1/PD-L1 pour renforcer l'efficacité d'une immunothérapie à base de lymphocytes T modifiés pour exprimer un récepteur antigénique chimérique

Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

Cherkassky, Leonid ; Morello, Aurore ; Villena-Vargas, Jonathan ; Feng, Yang ; Dimitrov, Dimiter S. ; Jones, David R. ; Sadelain, Michel ; Adusumilli, Prasad S.

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse [...]

A partir de données portant sur 103 échantillons tumoraux prélevés sur des patients atteints d'un cancer avancé du poumon ALK+, puis menée sur des lignées cellulaires, cette étude évalue notamment l'activité antitumorale d'un inhibiteur d'ALK dit de troisième génération, le lorlatinib

Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer

Gainor, Justin F. ; Dardaei, Leila ; Yoda, Satoshi ; Friboulet, Luc ; Leshchiner, Ignaty ; Katayama, Ryohei ; Dagogo-Jack, Ibiayi ; Gadgeel, Shirish ; Schultz, Katherine ; Singh, Manrose ; Chin, Emily ; Parks, Melissa ; Lee, Dana ; DiCecca, Richard H. ; Lockerman, Elizabeth ; Huynh, Tiffany ; Logan, Jennifer ; Ritterhouse, Lauren L. ; Le, Long P. ; Muniappan, Ashok ; Digumarthy, Subba ; Channick, Colleen ; Keyes, Colleen ; Getz, Gad ; Dias-Santagata, Dora ; Heist, Rebecca S. ; Lennerz, Jochen ; Sequist, Lecia V. ; Benes, Cyril H. ; Iafrate, A. John ; Mino-Kenudson, Mari ; Engelman, Jeffrey A. ; Shaw, Alice T.

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients [...]

Cet article passe en revue les travaux récents sur le développement de nouveaux traitements pour les patients atteints d'un cancer de la prostate résistant à la castration

Drug discovery in advanced prostate cancer: translating biology into therapy

Yap, Timothy A. ; Smith, Alan D. ; Ferraldeschi, Roberta ; Al-Lazikani, Bissan ; Workman, Paul ; de Bono, Johann S.

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. [...]

Menée sur un ensemble de lignées cellulaires de cancer colorectal présentant un gène BRAF muté, cette étude identifie divers mécanismes moléculaires associés à une résistance thérapeutique

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer

Oddo, Daniele ; Sennott, Erin M. ; Barault, Ludovic ; Valtorta, Emanuele ; Arena, Sabrina ; Cassingena, Andrea ; Filiciotto, Genny ; Marzolla, Giulia ; Elez, Elena ; van Geel, Robin M. J. M. ; Bartolini, Alice ; Crisafulli, Giovanni ; Boscaro, Valentina ; Godfrey, Jason T. ; Buscarino, Michela ; Cancelliere, Carlotta ; Linnebacher, Michael ; Corti, Giorgio ; Truini, Mauro ; Siravegna, Giulia ; Grasselli, Julieta ; Gallicchio, Margherita ; Bernards, Rene ; Schellens, Jan H. M. ; Tabernero, Josep ; Engelman, Jeffrey A. ; Sartore-Bianchi, Andrea ; Bardelli, Alberto ; Siena, Salvatore ; Corcoran, Ryan B. ; Di Nicolantonio, Federica

Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug [...]

Menée in vitro et in vivo sur des modèles de carcinome à cellules rénales, cette étude met en évidence des mécanismes par lesquels, en activant l'expression de la protéine OCT2, la décitabine sensibilise les cellules cancéreuses à une chimiothérapie à base d'oxaliplatine

Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin

Liu, Yanqing ; Zheng, Xiaoli ; Yu, Qinqin ; Wang, Hua ; Tan, Fuqing ; Zhu, Qianying ; Yuan, Lingmin ; Jiang, Huidi ; Yu, Lushan ; Zeng, Su

Renal cell carcinoma is a common cancer that is often resistant to chemotherapy. To address this, Liu et al. investigated the role of OCT2, a protein that normally transports oxaliplatin, a common chemotherapy drug, into cells. The authors found that OCT2 was epigenetically silenced in renal cancer and figured out the underlying mechanism, then designed a combination therapy with decitabine, a drug that reverses epigenetic silencing of OCT2, followed by oxaliplatin, and demonstrated its [...]

Menée in vitro et in vivo sur des modèles de cancer du sein triplement négatif, cette étude suggère l'intérêt d'une stratégie thérapeutique combinant le cétuximab et un composé inhibant une enzyme, l'acide gras synthase

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Giró-Perafita, Ariadna ; Palomeras, Sònia ; Lum, David H. ; Blancafort, Adriana ; Viñas, Gemma ; Oliveras, Glòria ; Pérez-Bueno, Ferran ; Sarrats, Ariadna ; Welm, Alana L. ; Puig, Teresa

Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling [...]

Mené sur 22 patients atteints d'un cancer de stade avancé (19 cas de cancer colorectal, 3 cas de cancer épidermoïde de la tête et du cou), cet essai de phase I évalue la dose maximale recommandée et l'activité antitumorale du lénalidomide en combinaison avec le cétuximab

A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer

Bertino, Erin M. ; McMichael, Elizabeth L. ; Mo, Xiaokui ; Trikha, Prashant ; Davis, Melanie ; Paul, Bonnie ; Grever, Michael ; Carson, William E. ; Otterson, M. D. Gregory A.

Monoclonal antibodies can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal (CRC) and head and neck squamous cell cancers (HNSCC). This trial [...]

Mené sur 28 patients atteints d'un cancer hématologique récidivant après une greffe allogénique de cellules souches hématopoïétiques, cet essai de phase I/Ib évalue la toxicité et l'activité antitumorale de l'ipilimumab

Ipilimumab for Patients with Relapse after Allogeneic Transplantation

Davids, Matthew S. ; Kim, Haesook T. ; Bachireddy, Pavan ; Costello, Caitlin ; Liguori, Rebecca ; Savell, Alexandra ; Lukez, Alexander P. ; Avigan, David ; Chen, Yi-Bin ; McSweeney, Peter ; LeBoeuf, Nicole R. ; Rooney, Michael S. ; Bowden, Michaela ; Zhou, Chensheng W. ; Granter, Scott R. ; Hornick, Jason L. ; Rodig, Scott J. ; Hirakawa, Masahiro ; Severgnini, Mariano ; Hodi, F. Stephen ; Wu, Catherine J. ; Ho, Vincent T. ; Cutler, Corey ; Koreth, John ; Alyea, Edwin P. ; Antin, Joseph H. ; Armand, Philippe ; Streicher, Howard ; Ball, Edward D. ; Ritz, Jerome ; Bashey, Asad ; Soiffer, Robert J.

BACKGROUND : Loss of donor-media ed immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte–associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS : We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab [...]

Mené sur 140 patients atteints d'un cancer du poumon non à petites cellules avec réarrangements ALK ayant progressé après un traitement impliquant une chimiothérapie à base de sels de platine et du crizotinib, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité du céritinib, notamment chez les patients présentant des métastases cérébrales

Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2

Crino, Lucio ; Ahn, Myung-Ju ; de Marinis, Filippo ; Groen, Harry J.M. ; Wakelee, Heather ; Hida, Toyoaki ; Mok, Tony ; Spigel, David ; Felip, Enriqueta ; Nishio, Makoto ; Scagliotti, Giorgio ; Branle, Fabrice ; Emeremni, Chetachi ; Quadrigli, Massimiliano ; Zhang, Jie ; Shaw, Alice T.

Purpose Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non–small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during [...]

A partir d'une revue systématique de la littérature (18 essais randomisés identifiés, ayant inclus un total de 6 756 patients atteints d'un cancer du poumon non à petites cellules), cette méta-analyse évalue l'efficacité des vaccins thérapeutiques et des immunothérapies cellulaires

The Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Dammeijer, Floris ; Lievense, Lysanne A. ; Veerman, G.D. Marijn ; Hoogsteden, Henk C. ; Hegmans, Joost P. ; Arends, Lidia R. ; Aerts, Joachim G.

Purpose Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non–small-cell lung cancer (NSCLC). Unfortunately, only a subgroup of patients responds and shows long-term survival to these therapies. Tumor vaccines and cellular immunotherapies could synergize with checkpoint blockade, but which of these treatments is most efficacious is unknown. In this meta-analysis, we assessed the efficacy of tumor vaccination and cellular [...]

Mené sur 1 132 patients atteints d'un cancer du poumon à petites cellules de stade étendu récemment diagnostiqué, cet essai randomisé international de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout d'ipilimumab à un traitement combinant étoposide et sels de platine

Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer

Reck, Martin ; Luft, Alexander ; Szczesna, Aleksandra ; Havel, Libor ; Kim, Sang-We ; Akerley, Wallace ; Pietanza, Maria Catherine ; Wu, Yi-Long ; Zielinski, Christoph ; Thomas, Michael ; Felip, Enriqueta ; Gold, Kathryn ; Horn, Leora ; Aerts, Joachim ; Nakagawa, Kazuhiko ; Lorigan, Paul ; Pieters, Anne ; Kong Sanchez, Teresa ; Fairchild, Justin ; Spigel, David

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum [...]

Mené sur 54 patients atteints d'un sarcome des os ou des tissus mous de stade avancé, cet essai de phase IB évalue la toxicité et l'activité antitumorale du selenexor, un inhibiteur de l'exportation de protéines nucléaires

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Gounder, Mrinal M. ; Zer, Alona ; Tap, William D. ; Salah, Samer ; Dickson, Mark A. ; Gupta, Abha A. ; Keohan, Mary Louise ; Loong, Herbert H. ; D’Angelo, Sandra P. ; Baker, Stephanie ; Condy, Mercedes ; Nyquist-Schultz, Kjirsten ; Tanner, Lanier ; Erinjeri, Joseph P. ; Jasmine, Francis H. ; Friedlander, Sharon ; Carlson, Robert ; Unger, Thaddeus J. ; Saint-Martin, Jean-Richard ; Rashal, Tami ; Ellis, Joel ; Kauffman, Michael ; Shacham, Sharon ; Schwartz, Gary K. ; Abdul Razak, Albiruni Ryan

Purpose We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m2, 50 mg/m2, or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was [...]

A partir d'une revue de la littérature (6 essais randomisés identifiés, ayant inclus un total de 1 155 patientes atteintes d'un cancer du sein HER2+), cette méta-analyse évalue l'efficacité d'un traitement néoadjuvant combinant lapatinib, trastuzumab et chimiothérapie

Dual Block with Lapatinib and Trastuzumab Versus Single-Agent Trastuzumab Combined with Chemotherapy as Neoadjuvant Treatment of HER2-Positive Breast Cancer: A Meta-analysis of Randomized Trials

Clavarezza, Matteo ; Puntoni, Matteo ; Gennari, Alessandra ; Paleari, Laura ; Provinciali, Nicoletta ; D’Amico, Mauro ; DeCensi, Andrea

Purpose: (Neo)adjuvant treatment with chemotherapy plus trastuzumab reduces recurrence and death risk in HER2-positive (HER2+) breast cancer. Randomized trials assessed HER2 dual block by adding lapatinib to trastuzumab and chemotherapy in the neoadjuvant setting using pathologic complete response (pCR) as the outcome measure. We conducted a meta-analysis of randomized trials testing neoadjuvant dual block with lapatinib and trastuzumab versus trastuzumab alone in HER2+ breast cancer. [...]

Menée sur des modèles sphéroïdes de cancer du pharynx, du côlon ou du poumon non à petites cellules et à l'aide de xénogreffes sur des modèles murins, cette étude montre que l'atovaquone, un antipaludique, augmente la sensibilité des cellules cancéreuses aux rayonnements ionisants en réduisant l'hypoxie de la tumeur

The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

Ashton, Thomas M. ; Fokas, Emmanouil ; Kunz-Schughart, Leoni A. ; Folkes, Lisa K. ; Anbalagan, Selvakumar ; Huether, Melanie ; Kelly, Catherine J. ; Pirovano, Giacomo ; Buffa, Francesca M. ; Hammond, Ester M. ; Stratford, Michael ; Muschel, Ruth J. ; Higgins, Geoff S. ; McKenna, William Gillies

Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In [...]

Mené sur 30 patients atteints d'un lymphome hodgkinien classique de stade précoce avec caractéristiques défavorables, cet essai multicentrique évalue l'efficacité, du point de vue de la survie sans progression à 1 an, et la toxicité d'un traitement comportant le brentuximab védotine, une chimiothérapie de type AVD et une radiothérapie des champs impliqués

Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma

Kumar, Anita ; Casulo, Carla ; Yahalom, Joachim ; Schöder, Heiko ; Barr, Paul M. ; Caron, Philip ; Chiu, April ; Constine, Louis S. ; Drullinsky, Pamela ; Friedberg, Jonathan W. ; Gerecitano, John F. ; Hamilton, Audrey ; Hamlin, Paul A. ; Horwitz, Steven M. ; Jacob, Alexandra G. ; Matasar, Matthew J. ; McArthur, Gianna N. ; McCall, Susan J. ; Moskowitz, Alison J. ; Noy, Ariela ; Palomba, Maria L. ; Portlock, Carol S. ; Straus, David J. ; VanderEls, Nicholas ; Verwys, Stephanie L. ; Yang, Joanna ; Younes, Anas ; Zelenetz, Andrew D. ; Zhang, Zhigang ; Moskowitz, Craig H.

Brentuximab Vedotin and AVD followed by ISRT is well tolerated, without significant pulmonary toxicity.Brentuximab Vedotin and AVD followed by ISRT is an effective therapy for unfavorable risk early stage HL, including bulky disease. This multicenter pilot study assessed the safety and efficacy of Brentuximab Vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gray (Gy) involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical [...]

Menée à partir de l'analyse de données cliniques portant sur 127 patients atteints d'un mélanome de stade avancé, cette étude multicentrique montre que l'ajout d'un traitement localisé (radiothérapie, électrochimiothérapie) à une immunothérapie par ipilimumab améliore la survie des patients

Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma

Theurich, Sebastian ; Rothschild, Sacha I. ; Hoffmann, Michael ; Fabri, Mario ; Sommer, Andrea ; Garcia-Marquez, Maria ; Thelen, Martin ; Schill, Catherine ; Merki, Ramona ; Schmid, Thomas ; Koeberle, Dieter ; Zippelius, Alfred ; Baues, Christian ; Mauch, Cornelia ; Tigges, Christian ; Kreuter, Alexander ; Borggrefe, Jan ; von Bergwelt-Baildon, Michael ; Schlaak, Max

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma [...]

Menée à partir des données d'un essai de phase III incluant 151 patients atteints d'un cancer du poumon non à petites cellules de stade III (durée médiane de suivi : 6,1 ans) et à partir d'une méta-analyse des données de 5 essais incluant au total 866 patients, cette étude évalue, du point de vue du taux de survie à 3 ans et de la survie globale à 1 an, l'intérêt d'ajouter de manière concomitante le paclitaxel à une radiothérapie thoracique en combinaison avec une chimiothérapie d'induction par sels de platine et paclitaxel

Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC

Ardizzoni, Andrea ; Tiseo, Marcello ; Boni, Luca ; Di Maio, Massimo ; Buffoni, Lucio ; Belvedere, Ornella ; Grossi, Francesco ; D'Alessandro, Vito ; de Marinis, Filippo ; Barbera, Santi ; Caroti, Cinzia ; Favaretto, Adolfo ; Cortinovis, Diego ; Morrica, Brunello ; Tixi, Lucia ; Ceschia, Tino ; Parisi, Salvatore ; Ricardi, Umberto ; Grimaldi, Andrea ; Loreggian, Lucio ; Navarria, Pierina ; Huber, Rudolf M. ; Belani, Chandra ; Bruswig, Paal Fr ; Scagliotti, Giorgio Vittorio ; Scolaro, Tindaro

Background : Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome. Material and methods : In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2 Gy thoracic irradiation (control arm) or by same radiotherapy with [...]

A partir d'une revue systématique de la littérature (4 études), cette méta-analyse évalue, du point de vue de la survie et de la toxicité, l'intérêt d'ajouter une chimiothérapie à une radiothérapie chez les patients atteints d'un cancer du poumon non à petites cellules de stade III et âgés de 70 ans ou plus

Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer : a systematic review and meta-analysis

Dawe, David E. ; Christiansen, David ; Swaminath, Anand ; Ellis, Peter M. ; Rothney, Janet ; Rabbani, Rasheda ; Abou-Setta, Ahmed M. ; Zarychanski, Ryan ; Mahmud, Salaheddin M.

In stage III non-small cell lung cancer (NSCLC), the standard of care in young patients is chemoradiotherapy, but this standard is not as clearly established for older patients. We aimed to determine the efficacy and harm associated with chemoradiotherapy versus radiotherapy alone in elderly (≥70 years), stage III NSCLC patients through a systematic review. We conducted a systematic search of MEDLINE, EMBASE, CENTRAL, Scopus, Web of Science and conference proceedings. Two reviewers [...]

Menée à partir des données de 12 essais portant au total sur 2 668 patients atteints d'un cancer du poumon à petites cellules de stade limité (durée médiane de suivi : 10 ans), cette méta-analyse évalue, dans de cadre d'un traitement combinant chimiothérapie et radiothérapie thoracique, l'effet du délai entre ces deux modalités thérapeutiques et de la durée de la radiothérapie sur la survie globale à 5 ans des patients et la toxicité du traitement

Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis

De Ruysscher, D. ; Lueza, B. ; Le Péchoux, C. ; Johnson, D. H. ; O'Brien, M. ; Murray, N. ; Spiro, S. ; Wang, X. ; Takada, M. ; Lebeau, B. ; Blackstock, W. ; Skarlos, D. ; Baas, P. ; Choy, H. ; Price, A. ; Seymour, L. ; Arriagada, R. ; Pignon, J-P.

Background : Chemotherapy combined with radiotherapy is the standard treatment of “limited-stage” small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and chemotherapy. Material and methods : We performed a meta-analysis of individual patient data in randomised trials comparing earlier versus later radiotherapy, or shorter vs. longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified [...]

Menée à partir de données portant sur 487 patients traités entre 2000 et 2013 pour un adénocarcinome de la prostate à haut risque de récidive (durée médiane de suivi : 4,6 ans ; score de Gleason 9-10), cette étude multicentrique compare, du point de vue de la survie spécifique et de la survie globale à 5 et 10 ans, l'efficacité d'une prostatectomie radicale et d'une radiothérapie externe en combinaison ou non avec une curiethérapie ou un traitement anti-androgénique

Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy : A Multi-institutional Comparative Analysis

Kishan, Amar U. ; Shaikh, Talha ; Wang, Pin-Chieh ; Reiter, Robert E. ; Said, Jonathan ; Raghavan, Govind ; Nickols, Nicholas G. ; Aronson, William J. ; Sadeghi, Ahmad ; Kamrava, Mitchell ; Demanes, David Jeffrey ; Steinberg, Michael L. ; Horwitz, Eric M. ; Kupelian, Patrick A. ; King, Christopher R.

Background : The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9–10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful [...]

Mené en France sur 265 patients atteints d'un cancer du moyen ou du bas rectum de stade cT3/T4 ou Tx N+ et traités entre 2012 et 2015, cet essai multicentrique de phase III évalue l'effet du délai (7 semaines ou 11 semaines) entre une chimioradiothérapie néoadjuvante et une intervention chirurgicale sur le taux de réponse pathologique complète

Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)

Lefevre, Jérémie H. ; Mineur, Laurent ; Kotti, Salma ; Rullier, Eric ; Rouanet, Philippe ; de Chaisemartin, Cécile ; Meunier, Bernard ; Mehrdad, Jafari ; Cotte, Eddy ; Desrame, Jérome ; Karoui, Mehdi ; Benoist, Stéphane ; Kirzin, Sylvain ; Berger, Anne ; Panis, Yves ; Piessen, Guillaume ; Saudemont, Alain ; Prudhomme, Michel ; Peschaud, Frédérique ; Dubois, Anne ; Loriau, Jérome ; Tuech, Jean-Jacques ; Meurette, Guillaume ; Lupinacci, Renato ; Goasgen, Nicolas ; Parc, Yann ; Simon, Tabassome ; Tiret, Emmanuel

Purpose : A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods : GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with [...]

Cet article passe en revue les études récentes concernant l'efficacité de l'hyperthermie régionale, en combinaison avec une chimiothérapie, pour traiter un sarcome des tissus mous à risque élevé de récidive

Regional hyperthermia for high-risk soft tissue sarcoma treatment : present status and next questions

Issels, Rolf ; Lindner, Lars H.

Purpose of review : Recent developments of neo-adjuvant chemotherapy treatment strategies for high-risk soft tissue sarcoma (STS) with special emphasis on regional hyperthermia (RHT) are reviewed. Recent findings : Attempts to improve outcomes using up-front strategies in addition to surgery have essentially focused on neo-adjuvant and adjuvant chemotherapy or preoperative radiochemotherapy. Unfortunately, the results are either confounded by retrospective analyses of nonrandomized studies with [...]

Cet article passe en revue les principales données concernant le traitement par radiothérapie, chirurgie et/ou thérapie ciblée de métastases cérébrales ayant pour origine un cancer du rein

Multimodality treatment of brain metastases from renal cell carcinoma in the era of targeted therapy

Maria, Bassanelli ; Antonella, Viterbo ; Michela, Roberto ; Silvana, Giacinti ; Anita, Staddon ; Anna Maria, Aschelter ; Chiara, D’Antonio ; Paolo, Marchetti

In patients with renal cancer, brain metastasis is associated with poor survival and high morbidity. Poor life expectancy is often associated with widespread extracranial metastases. In such patients, a multidisciplinary approach is paramount. Brain metastases-specific therapies may include surgery, radiosurgery, conventional radiation and targeted therapies (TT) or a combination of these treatments. Some factors are important prognostically when choosing the best strategy: performance status, [...]

Menée aux Etats-Unis à partir des données du registre national des cancers portant sur 3 753 patients atteints d'un carcinome urothélial métastatique de la vessie et ayant reçu plusieurs agents chimiothérapeutiques, cette étude évalue le bénéfice, en termes de survie globale, d'un traitement local agressif (cystectomie radicale, radiothérapie supérieure ou égale à 50 Gy) par rapport à un traitement conservateur (résection transurétrale de la tumeur, radiothérapie inférieure à 50 Gy)

Efficacy of High-Intensity Local Treatment for Metastatic Urothelial Carcinoma of the Bladder : A Propensity Score–Weighted Analysis From the National Cancer Data Base

Seisen, Thomas ; Sun, Maxine ; Leow, Jeffrey J. ; Preston, Mark A. ; Cole, Alexander P. ; Gelpi-Hammerschmidt, Francisco ; Hanna, Nawar ; Meyer, Christian P. ; Kibel, Adam S. ; Lipsitz, Stuart R. ; Nguyen, Paul L. ; Bellmunt, Joaquim ; Choueiri, Toni K. ; Trinh, Quoc-Dien

Purpose : Evidence from studies of other malignancies has indicated that aggressive local treatment (LT), even in the presence of metastatic disease, is beneficial. Against a backdrop of stagnant mortality rates for metastatic urothelial carcinoma of the bladder (mUCB) at presentation, we hypothesized that high-intensity LT of primary tumor burden, defined as the receipt of radical cystectomy or ≥ 50 Gy of radiation therapy delivered to the bladder, affects overall survival (OS). Patients and [...]

Menée sur des lignées cellulaires de carcinome épidermoïde de la tête et du cou et à l'aide d'une xénogreffe sur un modèle murin, cette étude montre que l'inhibition de la kinase CHK1 sensibilise les cellules tumorales à un traitement combinant de manière concomitante radiothérapie et chimiothérapie par paclitaxel

CHK1 inhibition radiosensitises head and neck cancers to paclitaxel-based chemoradiotherapy

Barker, Holly E. ; Patel, Radhika ; McLaughlin, Martin ; Schick, Ulrike ; Zaidi, Shane ; Nutting, Christopher M. ; Newbold, Katie L. ; Bhide, Shreerang ; Harrington, Kevin J.

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally-advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and [...]

Menée à l'aide d'une analyse protéomique et transcriptomique dans des lignées cellulaires de carcinome épidermoïde de la tête et du cou non lié au papillomavirus humain, puis menée sur plusieurs cohortes indépendantes de patients, cette étude met en évidence une association entre la surexpression de PTK2/FAK et la résistance des cellules tumorales aux rayonnements ionisants

Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer

Skinner, Heath D. ; Giri, Uma ; Yang, Liang ; Woo, Sang Hyeok ; Story, Michael D. ; Pickering, Curtis R. ; Byers, Lauren A. ; Williams, Michelle D. ; El-Naggar, Adel ; Wang, Jing ; Diao, Lixia ; Shen, Li ; Fan, You Hong ; Molkentine, David P. ; Beadle, Beth M. ; Meyn, Raymond E. ; Myers, Jeffrey N. ; Heymach, John V.

Purpose : Head and neck squamous cell carcinoma (HNSCC) is commonly treated with radiotherapy, and local failure after treatment remains the major cause of disease-related mortality. To date, human papillomavirus (HPV) is the only known clinically validated, targetable biomarkers of response to radiation in HNSCC. Experimental Design : We performed proteomic and transcriptomic analysis of targetable biomarkers of radioresistance in HPV-negative HNSCC cell lines in vitro, and tested whether [...]

A partir de 97 études précliniques ayant impliqué 1 761 animaux, cette méta-analyse évalue l'efficacité du sorafénib dans le traitement de divers types de cancer (carcinome hépatocellulaire, carcinome rénal, ...)

Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy

Mattina, James ; MacKinnon, Nathalie ; Henderson, Valerie C. ; Fergusson, Dean ; Kimmelman, Jonathan

The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response [...]

Cet article analyse les indications, les avantages et les inconvénients de la chirurgie laparoscopique assistée par robot dans la prise en charge des cancers gynécologiques

Evidence for the use of robotically assisted surgery in gynaecologic cancers

Ngô, Charlotte ; Cornou, Caroline ; Rossi, Léa ; Bats, Anne-Sophie ; Bensaid, Chérazade ; Frati, Albane ; Nos, Claude ; Lécuru, Fabrice

Purpose of review : Robotically assisted laparoscopy has been introduced in the armamentarium of gynaecologic oncology surgeons. A lot of studies compared robotic surgery and laparotomy when the real issue is to demonstrate the interest and added value of robotically assisted laparoscopy versus standard laparoscopy. In this review, we will describe the most meaningful indications and advantages of robotically assisted laparoscopy in gynaecologic oncology. Recent findings : The learning curve [...]

Cet article analyse les facteurs de risque et les facteurs pronostiques associés à différents types de carcinome épidermoïde récidivant de la vulve, puis présente les différentes options thérapeutiques

Risk factors and treatment for recurrent vulvar squamous cell carcinoma

Nooij, L. S. ; Brand, F. A. M. ; Gaarenstroom, K. N. ; Creutzberg, C. L. ; Hullu, J. A. de ; Poelgeest, M. I. E. van

Recurrent disease occurs in 12-37% of patients with vulvar squamous cell carcinoma (VSCC). Decisions about treatment of recurrent VSCC mainly depend on the location of the recurrence and previous treatment, resulting in individualized and consensus-based approaches. Most recurrences (40–80%) occur within 2 years after initial treatment. Currently, wide local excision is the treatment of choice for local recurrences. Isolated local recurrence of VSCC has a good prognosis, with reported 5-year [...]