Menée sur un modèle murin de mélanome des extrémités, cette étude évalue, par rapport au melphalan, l'efficacité et la toxicité d'un nouvel anticancéreux (CBL0137) administrable par perfusion isolée du membre atteint

Preclinical validation of a single-treatment infusion modality that can eradicate extremity melanomas

Kim, Minhyung ; Neznanov, Nickolay ; Wilfong, Chandler D ; Fleyshman, Daria I ; Purmal, Andrei A ; Haderski, Gary ; Stanhope-Baker, Patricia ; Burkhart, Catherine ; Gurova, Katerina V ; Gudkov, Andrei V. ; Skitzki, Joseph J

Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma, but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a non-genotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability. Here we report that CBL0137 delivered by ILP in a murine [...]

Menée à l'aide de modèles cellulaires tridimensionnels d'adénocarcinome canalaire du pancréas, cette étude montre que la composition et les caractéristiques rhéologiques de la matrice extra-cellulaire conditionnent la croissance et la motilité des cellules cancéreuses ainsi que leur réponse à une photothérapie dynamique

ECM Composition and Rheology Regulate Growth, Motility and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma

Cramer, Gwendolyn M ; Jones, Dustin P ; El Hamidi, Hamid ; Celli, Jonathan P

Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich PDAC stroma has been implicated as a barrier to drug penetration, though stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate [...]

Menée sur des lignées cellulaires de cancer de la prostate, cette étude montre qu'une radiothérapie fractionnée augmente la radiorésistance des cellules cancéreuses

Fractionated radiation exposure amplifies the radioresistant nature of prostate cancer cells

McDermott, N. ; Meunier, A. ; Mooney, B. ; Nortey, G. ; Hernandez, C. ; Hurley, S. ; Lynam-Lennon, N. ; Barsoom, S. H. ; Bowman, K. J. ; Marples, B. ; Jones, G. D. D. ; Marignol, L.

The risk of recurrence following radiation therapy remains high for a significant number of prostate cancer patients. The development of in vitro isogenic models of radioresistance through exposure to fractionated radiation is an increasingly used approach to investigate the mechanisms of radioresistance in cancer cells and help guide improvements in radiotherapy standards. We treated 22Rv1 prostate cancer cells with fractionated 2 Gy radiation to a cumulative total dose of 60 Gy. This process [...]

Menée à partir de données portant sur 546 patients atteints d'un carcinome hépatocellulaire ne correspondant pas aux critères de Milan (une seule tumeur avec taille inférieure ou égale à 5 cm ; plusieurs tumeurs avec taille inférieure ou égale à 3 cm), cette étude chinoise compare, du point de vue de la préservation des fonctions hépatiques, du taux de survie sans récidive et du taux de survie globale à 3 ans, l'intérêt d'une résection anatomique et d'une résection non anatomique

Anatomical versus non-anatomical liver resection for hepatocellular carcinoma exceeding Milan criteria

Li, S. Q. ; Huang, T. ; Shen, S. L. ; Hua, Y. P. ; Hu, W. J. ; Kuang, M. ; Peng, B. G. ; Liang, L. J.

Background : Liver resection is effective for hepatocellular carcinoma (HCC) exceeding the Milan criteria in selected patients. However, the benefit of anatomical resection (AR) versus non-anatomical resection (NAR) has not been clarified in this patient subgroup. This study aimed to compare outcomes between AR and NAR for HCC exceeding the Milan criteria. Methods : Data on consecutive patients with HCC exceeding the Milan criteria who underwent liver resection with curative intent over a [...]

Menée à partir de données portant sur 1 828 patients atteints d'un cancer du pancréas de stade localement avancé à la limite de la résécabilité, cette étude évalue, du point de vue de la durée de l'opération, de la morbidité chirurgicale, de la mortalité à 30 jours et de la survie globale à 5 ans, l'intérêt d'une pancréatectomie étendue par rapport à une pancréatectomie standard, puis identifie les facteurs associés à la mortalité péri-opératoire ou à la survie

Outcomes after extended pancreatectomy in patients with borderline resectable and locally advanced pancreatic cancer

Hartwig, W. ; Gluth, A. ; Hinz, U. ; Koliogiannis, D. ; Strobel, O. ; Hackert, T. ; Werner, J. ; Buchler, M. W.

Background : In the recent International Study Group of Pancreatic Surgery (ISGPS) consensus on extended pancreatectomy, several issues on perioperative outcome and long-term survival remained unclear. Robust data on outcomes are sparse. The present study aimed to assess the outcome of extended pancreatectomy for borderline resectable and locally advanced pancreatic cancer. Methods : A consecutive series of patients with primary pancreatic adenocarcinoma undergoing extended pancreatectomies, as [...]

Menée à partir de données portant sur 121 patients atteints d'un cancer rectal (durée médiane de suivi : 49 mois), cette étude multicentrique compare, du point de vue de la qualité de vie des patients et de la préservation de la fonction intestinale, l'intérêt d'une exérèse localisée et d'une exérèse totale du mésorectum après une chimioradiothérapie

Bowel function and quality of life after local excision or total mesorectal excision following chemoradiotherapy for rectal cancer

Pucciarelli, S. ; Giandomenico, F. ; De Paoli, A. ; Gavaruzzi, T. ; Lotto, L. ; Mantello, G. ; Barba, C. ; Zotti, P. ; Flora, S. ; Del Bianco, P.

Background : Local excision for rectal cancer is expected to offer a better functional outcome than conventional surgery. The aim of the present study was to compare quality of life and bowel function in patients with rectal cancer who underwent either local excision or conventional surgery after chemoradiotherapy. Methods : This was a retrospective multicentre study. Patients who underwent local excision were compared with those who had mesorectal excision. Quality of life and bowel function [...]

Mené sur 462 patients atteints d'un cancer colorectal de stade II ou III siégeant à moins de 12 cm de la marge anale et traité entre 2008 et 2013, cet essai multicentrique évalue, du point de vue de la qualité des marges de résection, la non infériorité d'une résection laparoscopique par rapport à une résection par voie ouverte

Outcomes of open vs laparoscopic rectal cancer resection

Roxburgh, C. S. ; Guillem, J. G.

Importance : Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. Objective : To determine whether laparoscopic resection is noninferior to open resection, as determined by gross pathologic and histologic evaluation of the resected proctectomy specimen. Design, Setting, and Participants : A multicenter, balanced, noninferiority, randomized trial enrolled patients between October 2008 and September 2013. [...]

Menée à partir des données 2004-2013 du registre national américain des cancers portant sur 2 082 patients atteints d'un liposarcome rétropéritonéal traité par résection (taille médiane de la tumeur : 22 cm), cette étude analyse l'intérêt d'une radiothérapie néoadjuvante pour améliorer la survie des patients

Preoperative radiotherapy in the management of retroperitoneal liposarcoma

Ecker, B. L. ; Peters, M. G. ; McMillan, M. T. ; Sinnamon, A. J. ; Zhang, P. J. ; Fraker, D. L. ; Levin, W. P. ; Roses, R. E. ; Karakousis, G. C.

Background : Histological subtype influences both prognosis and patterns of treatment failure in retroperitoneal sarcoma. Previous studies on the efficacy of neoadjuvant radiotherapy (NRT) have incorporated multiple histological types with heterogeneous tumour biology. The survival impact of NRT specifically for patients with retroperitoneal liposarcoma is poorly defined. Methods : Patients who underwent resection with curative intent for retroperitoneal liposarcoma and who received NRT or [...]

Cet article passe en revue les travaux récents ayant mis en oeuvre des techniques génomiques pour comprendre la réponse et la résistance aux immunothérapies, principalement aux inhibiteurs de points de contrôle

Genomic Approaches to Understanding Response and Resistance to Immunotherapy

Braun, David A. ; Burke, Kelly P. ; Van Allen, Eliezer M.

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all, and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are [...]

Menée sur des lignées cellulaires, des modèles murins et 24 patients atteints d'une leucémie myéloïde aiguë avec duplication interne en tandem FLT3-ITD, cette étude suggère l'intérêt d'un traitement combinant homoharringtonine et inhibiteur de FLT3-ITD

Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia

Lam, Stephen S. Y. ; Ho, Eric S. K. ; He, Bai-Liang ; Wong, Wui-Wing ; Cher, Chae-Yin ; Ng, Nelson K. L. ; Man, Cheuk-Him ; Gill, Harinder ; Cheung, Alice M. S. ; Ip, Ho-Wan ; So, Chi-Chiu ; Tamburini, Jérôme ; So, Chi Wai Eric ; Ho, Dona N. ; Au, Chun-Hang ; Chan, Tsun-Leung ; Ma, Edmond S. K. ; Liang, Raymond ; Kwong, Yok-Lam ; Leung, Anskar Y. H.

Acute myeloid leukemia is a difficult disease to treat under the best of circumstances, and the subtype containing internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) tends to be particularly challenging. Lam et al. performed a high-throughput drug screen and identified homoharringtonine as a candidate treatment for this type of leukemia and then confirmed its effectiveness in cancer cells, in mouse models, and in patients. The treatment showed promising results in a phase 2 [...]

Menée à l'aide de cultures cellulaires issues d'échantillons sanguins prélevés sur 21 patients atteints d'un lymphome à cellules du manteau, cette étude française met en évidence des mécanismes suggérant l'intérêt d'un traitement à base d'un anticorps monoclonal anti CD20 tel que l'obinutuzumab

Microenvironment-dependent proliferation and mitochondrial priming loss in mantle cell lymphoma is overcome by anti-CD20

Chiron, David ; Bellanger, Céline ; Papin, Antonin ; Tessoulin, Benoît ; Dousset, Christelle ; Maïga, Sophie ; Moreau, Anne ; Esbelin, Julie ; Trichet, Valérie ; Chen-Kiang, Selina ; Moreau, Philippe ; Touzeau, Cyrille ; Le Gouill, Steven ; Amiot, Martine ; Pellat-Deceunynck, Catherine

CD40L plus cytokines induces cell cycle progression and loss of mitochondrial priming leading to drug resistance in MCL.CD40L plus cytokines mimics in situ molecular profiles and allows the development of new approaches by integrating the role of the microenvironment. Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies [...]

Menée in vitro et in vivo sur des modèles de cancer du poumon non à petites cellules présentant un gène KRAS muté, cette étude met en évidence des mécanismes suggérant l'intérêt thérapeutique des inhibiteurs de XPO1

XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer

Kim, Jimi ; McMillan, Elizabeth ; Kim, Hyun Seok ; Venkateswaran, Niranjan ; Makkar, Gurbani ; Rodriguez-Canales, Jaime ; Villalobos, Pamela ; Neggers, Jasper Edgar ; Mendiratta, Saurabh ; Wei, Shuguang ; Landesman, Yosef ; Senapedis, William ; Baloglu, Erkan ; Chow, Chi-Wan B. ; Frink, Robin E. ; Gao, Boning ; Roth, Michael ; Minna, John D. ; Daelemans, Dirk ; Wistuba, Ignacio I. ; Posner, Bruce A. ; Scaglioni, Pier Paolo ; White, Michael A.

The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal [...]

A partir d'échantillons sanguins prélevés sur des patients atteints d'un cancer métastatique de la prostate et inclus dans deux essais cliniques évaluant l'ipilimumab, cette étude identifie une expansion clonale de lymphocytes T CD8 avant l'apparition d'événements indésirables sévères de nature immunitaire

Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities

Subudhi, Sumit K. ; Aparicio, Ana ; Gao, Jianjun ; Zurita, Amado J. ; Araujo, John C. ; Logothetis, Christopher J. ; Tahir, Salahaldin A. ; Korivi, Brinda R. ; Slack, Rebecca S. ; Vence, Luis ; Emerson, Ryan O. ; Yusko, Erik ; Vignali, Marissa ; Robins, Harlan S. ; Sun, Jingjing ; Allison, James P. ; Sharma, Padmanee

Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead to prolonged hospitalizations or fatalities. Early intervention is necessary to minimize morbidities that occur with severe irAEs. However, correlative biomarkers are currently [...]

Menée sur un ensemble de lignées cellulaires et à l'aide de xénogreffes de cancer du sein, cette étude met en évidence une activité antitumorale de l'ibrutinib, notamment pour les cancers HER2+

Ibrutinib inhibits ErbB receptor tyrosine kinases and HER2-amplified breast cancer cell growth

Chen, Jun ; Kinoshita, Taisei ; Sukbuntherng, Juthamas ; Chang, Betty Y. ; Elias, Laurence

Ibrutinib is a potent, small-molecule Bruton's tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among [...]

Mené sur 37 patients d'origine asiatique et atteints d'un carcinome hépatocellulaire de stade avancé, cet essai de phase I évalue les caractéristiques pharmacocinétiques, la dose maximale tolérée et l'activité antitumorale du sélumétinib combiné au sorafénib

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC)

Tai, W. M. ; Yong, W. P. ; Lim, C. ; Low, L. S. ; Tham, C. K. ; Koh, T. S. ; Ng, Q. S. ; Wang, W. W. ; Wang, L. Z. ; Hartano, S. ; Thng, C. H. ; Huynh, H. ; Lim, K. T. ; Toh, H. C. ; Goh, B. C. ; Choo, S. P.

Background : Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). [...]

A partir d'une revue systématique de la littérature (27 études, 24 178 participants), cette méta-analyse évalue l'efficacité, du point de vue de la survie sans récidive, de la survie globale et de la survie spécifique, de la metformine en traitement adjuvant pour les patients atteints de cancer, notamment d'un cancer de la prostate ou du côlon-rectum

Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis

Coyle, C. ; Cafferty, F. H. ; Vale, C. ; Langley, R. E.

Background : Metformin use has been associated with a reduced risk of developing cancer and an improvement in overall cancer survival rates in meta-analyses, but, to date, evidence to support the use of metformin as an adjuvant therapy in individual cancer types has not been presented. Patients and methods : We systematically searched research databases, conference abstracts and trial registries for any studies reporting cancer outcomes for individual tumour types in metformin users compared [...]

Mené sur 49 patients (phase I) puis sur 44 patients âgés de moins de 18 ans et atteints d'une leucémie lymphoblastique aiguë réfractaire ou récidivante (phase II), cet essai de phase I/II évalue la dose maximale tolérée puis l'efficacité, du point de vue du taux de rémission complète, du blinatumomab

Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

von Stackelberg, Arend ; Locatelli, Franco ; Zugmaier, Gerhard ; Handgretinger, Rupert ; Trippett, Tanya M. ; Rizzari, Carmelo ; Bader, Peter ; O’Brien, Maureen M. ; Brethon, Benoît ; Bhojwani, Deepa ; Schlegel, Paul Gerhardt ; Borkhardt, Arndt ; Rheingold, Susan R. ; Cooper, Todd Michael ; Zwaan, Christian M. ; Barnette, Phillip ; Messina, Chiara ; Michel, Gérard ; DuBois, Steven G. ; Hu, Kuolung ; Zhu, Min ; Whitlock, James A. ; Gore, Lia

Purpose : Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods : This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. [...]

Mené en France sur 100 patients atteints d'une leucémie myéloïde chronique, cet essai analyse les effets à long terme de l'interruption d'un traitement par imatinib (durée médiane de suivi : 77 mois après l'arrêt)

Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia

Etienne, Gabriel ; Guilhot, Joëlle ; Rea, Delphine ; Rigal-Huguet, Françoise ; Nicolini, Franck ; Charbonnier, Aude ; Guerci-Bresler, Agnes ; LEGROS, Laurence ; Varet, Bruno ; Gardembas, Martine ; Dubruille, Viviane ; Tulliez, Michel ; Noel, Marie-Pierre ; Ianotto, Jean-Christophe ; Villemagne, Bruno ; Carré, Martin ; Guilhot, François ; Rousselot, Philippe ; Mahon, François-Xavier

Purpose : Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods : IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse [...]

Mené sur 22 patients atteints d'un lymphome folliculaire, cet essai de phase I évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité d'un traitement combinant rituximab, lénalidomide et ibrutinib

Phase I trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103

Ujjani, Chaitra S. ; Jung, Sin-Ho ; Pitcher, Brandelyn ; Martin, Peter ; Park, Steven I. ; Blum, Kristie A. ; Smith, Sonali M. ; Czuczman, Myron ; Davids, Matthew S. ; Levine, Ellis ; Lewis, Lionel D. ; Smith, Scott E. ; Bartlett, Nancy L. ; Leonard, John P. ; Cheson, Bruce D.

The combination of rituximab, lenalidomide, and ibrutinib is associated with a high incidence of rash in follicular lymphoma (all grades 82%).Efficacy of the triplet appears similar to rituximab-lenalidomide in the same patient population. Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with [...]

Mené sur 481 patients atteints d'un lymphome diffus à grandes cellules B à haut risque de récidive, cet essai de phase III évalue l'efficacité, du point de vue de la survie sans évènement à 3 ans, d'un protocole thérapeutique combinant rituximab, cyclophosphamide, doxorubicine, vincristine et prednisone (R-CHOP) par rapport à un traitement combinant rituximab et chimiothérapie séquentielle à hautes doses (R-HDS) associée à une greffe autologue de celllules souches

Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas

Cortelazzo, Sergio ; Tarella, Corrado ; Gianni, Alessandro Massimo ; Ladetto, Marco ; Barbui, Anna Maria ; Rossi, Andrea ; Gritti, Giuseppe ; Corradini, Paolo ; Di Nicola, Massimo ; Patti, Caterina ; Mulé, Antonino ; Zanni, Manuela ; Zoli, Valerio ; Billio, Atto ; Piccin, Andrea ; Negri, Giovanni ; Castellino, Claudia ; Di Raimondo, Francesco ; Ferreri, Andrés J.M. ; Benedetti, Fabio ; La Nasa, Giorgio ; Gini, Guido ; Trentin, Livio ; Frezzato, Maurizio ; Flenghi, Leonardo ; Falorio, Simona ; chilosi, marco ; Bruna, Riccardo ; Tabanelli, Valentina ; Pileri, Stefano ; Masciulli, Arianna ; Delaini, Federica ; Boschini, Cristina ; Rambaldi, Alessandro

Purpose : The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods : From June 2005 to June 2011, [...]

Mené en Chine sur 42 patients atteints d'un lymphome à cellules NK/T de stade avancé récemment diagnostiqué, cet essai multicentrique randomisé évalue l'efficacité, du point de vue de la survie sans progression, de deux régimes de chimiothérapie, l'un à base de dexaméthasone, cisplatine, gemcitabine et pégaspargase (DDGP), et l'autre à base de vexaméthasone, méthotrexate, ifosfamide, L-asparaginase et étoposide (SMILE)

DDGP versus SMILE in Newly Diagnosed Advanced Natural Killer/T-Cell Lymphoma: A Randomized Controlled, Multicenter, Open-label Study in China

Li, Xin ; Cui, Yingying ; Sun, Zhenchang ; Zhang, Lei ; Li, Ling ; Wang, Xinhua ; Wu, Jingjing ; Fu, Xiaorui ; Ma, Wang ; Zhang, Xudong ; Chang, Yu ; Nan, Feifei ; Li, Wencai ; Su, Liping ; Wang, Jinghua ; Xue, Hongwei ; Zhang, Mingzhi

Purpose: Optimal treatment strategies for advanced natural killer/T (NK/T)-cell lymphoma have not been fully defined. We compared the safety and efficacy of DDGP and SMILE regimens for advanced NK/T-cell lymphoma in a randomized controlled, multicenter, and open-label clinical trial. Experimental Design: Patients were newly diagnosed in stages III–IV and had performance scores in 0 to 2. Six cycles of DDGP (dexamethasone, cisplatin, gemcitabline, and pegaspargase) or SMILE (dexamethasone, [...]

A partir d'une revue systématique de la littérature, cette étude fait le point sur l'utilisation de l'élotuzumab et du daratumumab dans la prise en charge des patients atteints d'un myélome multiple et évalue l'intérêt de ces anticorps monoclonaux lorsqu'ils sont combinés avec des inhibiteurs du protéasome ou des agents immunomodulateurs

How to Integrate Elotuzumab and Daratumumab Into Therapy for Multiple Myeloma

Hofmeister, Craig C. ; Lonial, Sagar

Purpose : Treatment options and outcomes for patients with multiple myeloma have dramatically improved over the past decade with new agents and drug targets for patients at all stages of disease. Incorporation of newly approved monoclonal antibodies is a clinical challenge because the trials used to gain approval are relatively limited in scope and may be less helpful for patients treated in the United States. This article will review data on the use of elotuzumab and daratumumab and provide a [...]

Mené sur 162 patients atteints d'un carcinome épidermoïde de l'œsophage de stade localement avancé et résécable, cet essai multicentrique de phase II évalue l'efficacité, du point de vue de la survie sans progression, de deux protocoles de chimiothérapie néoadjuvante, l'un à base de cisplatine, fluorouracil et docétaxel, l'autre à base de cisplatine, fluorouracil et adriamycine

Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus Adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003)

Yamasaki, M ; Yasuda, T ; Yano, M ; Hirao, M ; Kobayashi, K ; Fujitani, K ; Tamura, S ; Kimura, Y ; Miyata, H ; Motoori, M ; Shiraishi, O ; Makino, T ; Satoh, T ; Mori, M ; Doki, Y

Background: This phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment for patients with [...]

Mené sur 44 patients atteints d'un cancer du poumon à petites cellules récidivant, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du linsitinib par rapport au topotécan

A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer

Chiappori, Alberto A. ; Otterson, Gregory A. ; Dowlati, Afshin ; Traynor, Anne M. ; Horn, Leora ; Owonikoko, Taofeek K. ; Ross, Helen J. ; Hann, Christine L. ; Abu Hejleh, Taher ; Nieva, Jorge ; Zhao, Xiuhua ; Schell, Michael ; Sullivan, Daniel M.

Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC.Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC [...]

Menée à partir de données portant sur 136 patients atteints d'un cancer du poumon non à petites cellules ALK+ présentant des métastases cérébrales et inclus dans deux essais de phase II, cette étude évalue l'efficacité de l'alectinib du point de vue du taux de réponse objective évalué par un comité indépendant

Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non–Small-Cell Lung Cancer

Gadgeel, Shirish M. ; Shaw, Alice T. ; Govindan, Ramaswamy ; Gandhi, Leena ; Socinski, Mark A. ; Camidge, D. Ross ; De Petris, Luigi ; Kim, Dong-Wan ; Chiappori, Alberto ; Moro-Sibilot, Denis L. ; Duruisseaux, Michael ; Crino, Lucio ; De Pas, Tommaso ; Dansin, Eric ; Tessmer, Antje ; Yang, James Chih-Hsin ; Han, Ji-Youn ; Bordogna, Walter ; Golding, Sophie ; Zeaiter, Ali ; Ou, Sai-Hong Ignatius

Purpose : Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non–small-cell lung cancer (NSCLC). Patients and Methods : Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib [...]

Mené sur 40 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cet essai de phase II identifie des mécanismes de résistance à un traitement combinant abitérone et dutastéride

A phase II trial of abiraterone combined with dutasteride for men with metastatic castration-resistant prostate cancer

Taplin, Mary-Ellen ; McKay, Rana R ; Werner, Lillian ; Mostaghel, Elahe A ; Lis, Rosina T. ; Voznesensky, Olga ; Zhang, Zhenwei ; Marck, Brett ; Matsumoto, Alvin M. ; Domachevsky, Liran ; Zukotynski, Katherine A. ; Bhasin, Manoj K ; Bubley, Glenn J. ; Montgomery, Bruce ; Kantoff, Philip W. ; Balk, Steven P.

Purpose: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. Experimental Design: Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this [...]

Mené sur 226 patients atteints d'un carcinome papillaire métastatique du rein, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, de l'évérolimus en traitement de première ligne

Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis

Escudier, Bernard ; Molinié, Vincent ; Bracarda, Sergio ; Maroto, Pablo ; Szczylik, Cezary ; Nathan, Paul ; Négrier, Sylvie ; Weiss, Claudia ; Porta, Camillo ; Grünwald, Viktor ; Albiges, Laurence

Background : Papillary histology accounts for 10–15% of renal cell carcinoma (RCC), and treatment options for patients with this subtype are limited. The RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) study evaluated first-line everolimus in patients with papillary metastatic RCC (mRCC). Methods : This phase 2 trial enrolled previously untreated patients with type 1 or type 2 papillary mRCC. Papillary histology was confirmed by central review and [...]

Mené sur 32 patients atteints d'un sarcome de Kaposi symptomatique, avec ou sans infection par le VIH, cet essai de phase I/II évalue les caractéristiques pharmacocinétiques, la tolérabilité et l'efficacité, du point de vue du taux de réponse tumorale et de la qualité de vie, du pomalidomide, un agent immunomodulateur dispensé par voie orale

Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study

Polizzotto, Mark N. ; Uldrick, Thomas S. ; Wyvill, Kathleen M. ; Aleman, Karen ; Peer, Cody J. ; Bevans, Margaret ; Sereti, Irini ; Maldarelli, Frank ; Whitby, Denise ; Marshall, Vickie ; Goncalves, Priscila H. ; Khetani, Vikram ; Figg, William D. ; Steinberg, Seth M. ; Zeldis, Jerome B. ; Yarchoan, Robert

Purpose : Kaposi's sarcoma (KS) is a multicentric tumor caused by Kaposi's sarcoma–associated herpesvirus. Unmet needs include therapies that are oral, anthracycline sparing, and deliverable in resource-limited settings. We evaluated pomalidomide, an oral immune modulatory agent, in patients with symptomatic KS. Methods : The primary objectives were to assess tolerability, pharmacokinetics, and activity. Initial dosage level was 5 mg once per day for 21 days per 28-day cycle, with a [...]

Mené sur 27 patients atteints d'un neuroblastome à haut risque, cet essai de phase I/Ib évalue l'efficacité, du point de vue de la survie sans progression à long terme, et la toxicité de la périfosine en monothérapie dispensée par voie orale

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma

Kushner, Brian H. ; Cheung, Nai-Kong V. ; Modak, Shakeel ; Becher, Oren J. ; Basu, Ellen M. ; Roberts, Stephen S. ; Kramer, Kim ; Dunkel, Ira J.

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50–75 mg m−2 day−1 after a [...]

Menée sur des lignées cellulaires de cancer du poumon, du côlon ou du foie, cette étude montre qu'un traitement combinant décitabine et rayonnements ionisants peut augmenter la sensibilité des cellules tumorales à la cytotoxicité des lymphocytes T

Combination treatment with decitabine and ionizing radiation enhances tumor cells susceptibility of T cells

Son, Cheol-Hun ; Lee, Hong-Rae ; Koh, Eun-Kyoung ; Shin, Dong-Yeok ; Bae, Jae-Ho ; Yang, Kwangmo ; Park, You-Soo

Decitabine has been found to have anti-metabolic and anti-tumor activities in various tumor cells. Recently, the use of decitabine in combination with other conventional therapies reportedly resulted in improved anti-tumor activity against various tumors. Ionizing radiation (IR) is widely used as a cancer treatment. Decitabine and IR improve immunogenicity and susceptibility of tumor cells to immune cells by up-regulating the expression of various molecules such as major histocompatibility [...]

Menée à partir des données d'un essai portant sur 482 patients atteints d'un cancer du poumon non à petites cellules de stade localement avancé et ayant reçu un traitement comportant une radiothérapie et une chimiothérapie concomitante par carboplatine-paclitaxel en combinaison ou non avec le cétuximab (durée médiane de suivi : 21,3 mois), cette étude compare l'efficacité, du point de vue de la survie globale à 2 ans, et la toxicité d'une radiothérapie avec modulation d'intensité et d'une radiothérapie externe conformationnelle 3D

Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non–Small-Cell Lung Cancer : A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial

Chun, Stephen G. ; Hu, Chen ; Choy, Hak ; Komaki, Ritsuko U. ; Timmerman, Robert D. ; Schild, Steven E. ; Bogart, Jeffrey A. ; Dobelbower, Michael C. ; Bosch, Walter ; Galvin, James M. ; Kavadi, Vivek S. ; Narayan, Samir ; Iyengar, Puneeth ; Robinson, Clifford G. ; Wynn, Raymond B. ; Raben, Adam ; Augspurger, Mark E. ; MacRae, Robert M. ; Paulus, Rebecca ; Bradley, Jeffrey D.

Purpose : Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non–small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods : A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG [...]

Mené sur 123 enfants ou adolescents atteints d'un médulloblastome métastatique diagnostiqué entre 2001 et 2007 (âge médian : 8,2 ans ; durée médiane de suivi : 5,4 ans), cet essai évalue, en fonction des caractéristiques cliniques ou biologiques de la tumeur, la survie sans événement et la survie globale à 5 ans après un traitement comportant une chimiothérapie d'induction, une radiothérapie crânio-spinale hypofractionnée avec escalade de doses et une chimiothérapie d'entretien

Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters

von Bueren, André O. ; Kortmann, Rolf-Dieter ; von Hoff, Katja ; Friedrich, Carsten ; Mynarek, Martin ; Müller, Klaus ; Goschzik, Tobias ; zur Mühlen, Anja ; Gerber, Nicolas ; Warmuth-Metz, Monika ; Soerensen, Niels ; Deinlein, Frank ; Benesch, Martin ; Zwiener, Isabella ; Kwiecien, Robert ; Faldum, Andreas ; Bode, Udo ; Fleischhack, Gudrun ; Hovestadt, Volker ; Kool, Marcel ; Jones, David ; Northcott, Paul ; Kuehl, Joachim ; Pfister, Stefan ; Pietsch, Torsten ; Rutkowski, Stefan

Purpose : To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods : Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results : In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year [...]

Cet article analyse les enjeux associés au rôle des comités de surveillance et de suivi dans l'évaluation des risques et bénéfices d'un essai clinique en cours

Data Monitoring Committees — Expect the Unexpected

DeMets, David L. ; Ellenberg, Susan S.

In the five decades since the completion of the Greenberg Report recommendations in 1967 (which were later published), independent groups of experts have monitored the progress of many clinical trials for early definitive evidence of benefit, convincing evidence of harm, or sufficient evidence of no potential benefit to render continuation of the trial to be futile. Such monitoring is motivated primarily by an ethical imperative; for trials of treatments intended to prevent or delay serious [...]

Cet article passe en revue les travaux récents sur les modèles murins pour la recherche en immuno-oncologie

Mouse models in oncoimmunology

Zitvogel, Laurence ; Pitt, Jonathan M. ; Daillère, Romain ; Smyth, Mark J. ; Kroemer, Guido

Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies [mdash] each with their specific advantages and difficulties [mdash] have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from [...]

A partir d'une revue systématique de la littérature (5 études incluant au total 540 patients), cette méta-analyse évalue, chez les patients atteints d'une petite tumeur neuroendocrine asymptomatique sporadique et non fonctionnelle du pancréas, la possibilité de remplacer l'intervention chirurgicale par une surveillance médicale active

Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms

Partelli, S. ; Cirocchi, R. ; Crippa, S. ; Cardinali, L. ; Fendrich, V. ; Bartsch, D. K. ; Falconi, M.

Background : The incidence of asymptomatic, sporadic, small non-functioning pancreatic neuroendocrine neoplasms (NF-PNENs) has increased in recent decades. Conservative treatment has been advocated for these tumours. The aim of this study was systematically to evaluate the literature on active surveillance and to compare this with surgical management for asymptomatic sporadic small NF-PNENs. Methods : PubMed, Embase and the Cochrane Library were searched systematically for studies that compared [...]

Cet article passe en revue les différentes modalités thérapeutiques pour les tumeurs à cellules plasmacytoïdes dendritiques blastiques

A critical review of treatment modalities for blastic plasmacytoid dendritic cell neoplasm

Falcone, Umberto ; Sibai, Hassan ; Deotare, Uday

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursors of plasmacytoid dendritic cells. It is a rare disease presenting across all ages with either skin or both skin and bone marrow involvement often conferring a poor prognosis. Though localized radiation has been used before, acute leukemia based regimens, remains the treatment of choice for induction of remission. Hematopoietic stem cell transplant, either autologous or allogeneic, is [...]

Cette étude passe en revue l'évolution de l'utilisation de la chimiothérapie pour prendre en charge les patients atteints d'un cancer de la prostate métastatique et met en avant l'intérêt d'y avoir recours de façon précoce en traitement de première ligne

Early Use of Chemotherapy in Metastatic Prostate Cancer

Markowski, Mark C. ; Carducci, Michael A.

Highlights : •The optimal sequence of therapies for metastatic prostate cancer is unknown •Chemotherapy is commonly deferred in castration resistant prostate cancer •Recent data favors early use of chemotherapy in hormone sensitive disease Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose about the optimal sequence of these agents. Until recently, chemotherapy has been deferred [...]

Cet article passe en revue les traitements récents, en particulier les inhibiteurs de points de contrôle immunitaire et les agents ciblant le récepteur FGFR, pour les patients atteints d'un carcinome urothélial localement avancé ou métastatique

Targeting fibroblast growth factor receptors and Immune checkpoint inhibitors for the treatment of advanced bladder Cancer : New direction and New Hope

Morales-Barrera, Rafael ; Suárez, Cristina ; Castro, Ana Martínez de ; Racca, Fabricio ; Valverde, Claudia ; Maldonado, Xavier ; Bastaros, Juan Maria ; Morote, Juan ; Carles, Joan

Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients [...]