Cet article analyse les perspectives offertes par les nouvelles approches thérapeutiques en radio-oncologie

Emerging Treatment Paradigms in Radiation Oncology

Le, Quynh-Thu ; Shirato, Hiroki ; Giaccia, Amato J. ; Koong, Albert C.

Rapid advancements in radiotherapy and molecularly targeted therapies have resulted in the development of potential paradigm-shifting use of radiotherapy in the treatment of cancer. In this review, we will discuss some of the most promising therapeutic approaches in the field of radiation oncology. These strategies include the use of highly targeted stereotactic radiotherapy and particle therapy as well as combining radiotherapy with agents that modulate the DNA damage response, augment the [...]

Menée à partir des données de deux essais de phase III incluant au total 58 patients atteints d'un cancer du poumon non à petites cellules de stade I, cette étude compare, du point de vue de la survie globale, l'efficacité d'une radiothérapie stéréotaxique ablative (durée médiane de suivi : 40,2 mois) et d'une lobectomie avec curage ganglionnaire du médiastin (durée médiane de suivi : 35,4 mois)

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

Chang, Joe Y. ; Senan, Suresh ; Paul, Marinus A. ; Mehran, Reza J. ; Louie, Alexander V. ; Balter, Peter ; Groen, Harry J. M. ; McRae, Stephen E. ; Widder, Joachim ; Feng, Lei ; van den Borne, Ben E. E. M. ; Munsell, Mark F. ; Hurkmans, Coen ; Berry, Donald A. ; van Werkhoven, Erik ; Kresl, John J. ; Dingemans, Anne-Marie ; Dawood, Omar ; Haasbeek, Cornelis J. A. ; Carpenter, Larry S. ; De Jaeger, Katrien ; Komaki, Ritsuko ; Slotman, Ben J. ; Smit, Egbert F. ; Roth, Jack A.

Background : The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. [...]

Menée sur 55 patients atteints d'un cancer récidivant de la prostate traité entre 2007 et 2012 (durée médiane de suivi : 36 mois), cette étude évalue l'efficacité, du point de vue de la récidive biochimique, de la survie sans métastase et de la survie spécifique, et la sécurité d'une prostatectomie radicale de sauvetage

Salvage radical prostatectomy for recurrent prostate cancer: verification of European Association of Urology guideline criteria

Mandel, Philipp ; Steuber, Thomas ; Ahyai, Sascha ; Kriegmair, Maximilian ; Schiffmann, Jonas ; Boehm, Katharina ; Heinzer, Hans ; Michl, Uwe ; Schlomm, Thorsten ; Haese, Alexander ; Huland, Hartwig ; Graefen, Markus ; Tilki, Derya

Objective : To analyse oncological and functional outcomes of salvage radical prostatectomy (SRP) in patients with recurrent prostate cancer and to compare outcomes of patients within and outside the European Association of Urology (EAU) guideline criteria (organ-confined prostate cancer ≤T2b, Gleason score ≤7 and preoperative PSA level <10 ng/mL) for SRP. Patients and Methods : In all, 55 patients who underwent SRP from January 2007 to December 2012 were retrospectively analysed. Kaplan–Meier [...]

Menée à partir des données du registre national américain des cancers portant sur 3 540 patients atteints d'un cancer de la prostate avec envahissement ganglionnaire, cette étude évalue, du point de vue de la survie globale à 5 ans, l'intérêt d'ajouter une radiothérapie à un traitement anti-androgénique

Androgen Deprivation With or Without Radiation Therapy for Clinically Node-Positive Prostate Cancer

Lin, Chun Chieh ; Gray, Phillip J. ; Jemal, Ahmedin ; Efstathiou, Jason A.

Background : Clinically lymph node–positive (cN+) prostate cancer (PCa) is an often-fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. Methods : Patients with cN+ PCa and without distant metastases [...]

Menée sur 810 patients atteints d'un cancer de la prostate à risque élevé de récidive et traités par prostatectomie radicale assistée par robot et curage ganglionnaire pelvien, cette étude évalue la performance d'un nomogramme, intégrant 4 paramètres clinicopathologiques dont le niveau sérique du PSA et le score de Gleason, pour prédire les résultats pathologiques

Predicting pathological outcomes in patients undergoing robot-assisted radical prostatectomy for high-risk prostate cancer: a preoperative nomogram

Abdollah, Firas ; Klett, Dane E. ; Sood, Akshay ; Sammon, Jesse D. ; Pucheril, Daniel ; Dalela, Deepansh ; Diaz, Mireya ; Peabody, James O. ; Trinh, Quoc-Dien ; Menon, Mani

Objective : To identify which high-risk patients with prostate cancer may harbour favourable pathological outcomes at radical prostatectomy (RP). Patients and methods : We evaluated 810 patients with high-risk prostate cancer, defined as having one or more of the following: PSA level of >20 ng/mL, Gleason score ≥8, clinical stage ≥T2c. Patients underwent robot-assisted RP (RARP) with pelvic lymph node dissection, between 2003 and 2012, in one centre. Only 1.6% (13/810) of patients received any [...]

Mené sur 627 patientes âgées de 70 ans ou plus et atteintes d'un cancer du sein de stade pT1/2cN0 traité par quadrantectomie puis tamoxifène, cet essai évalue, en fonction du sous-type moléculaire de la tumeur, l'intérêt d'ajouter une radiothérapie au traitement pour réduire le risque à 15 ans de récidive ipsilatérale, de métastases distantes ou de décès par la maladie

Omission of radiotherapy in elderly patients with early breast cancer: 15-Year results of a prospective non-randomised trial

Martelli, Gabriele ; Boracchi, Patrizia ; Guzzetti, Eleonora ; Marano, Giuseppe ; Lozza, Laura ; Agresti, Roberto ; Ferraris, Cristina ; Piromalli, Domenico ; Greco, Marco

Background : Whether radiotherapy (RT) is beneficial in elderly (>= 70 years) patients undergoing conservative surgery for early breast cancer has long been controversial. Recent randomised trials show that most elderly patients do not benefit from RT. We started a prospective non-randomised trial to address this issue in 1987 and now present results for the 627 consecutive pT1/2cN0 patients recruited, and treated by conservative surgery (quadrantectomy) and tamoxifen, and assigned non-randomly [...]

Menée in vitro et in vivo, cette étude met en évidence l'activité antitumorale d'un anticorps bispécifique anti CD20/CD3 pour le traitement des patients atteints d'un cancer des lymphocytes B

Anti-CD20/CD3 T cell–dependent bispecific antibody for the treatment of B cell malignancies

Sun, Liping L. ; Ellerman, Diego ; Mathieu, Mary ; Hristopoulos, Maria ; Chen, Xiaocheng ; Li, Yijin ; Yan, Xiaojie ; Clark, Robyn ; Reyes, Arthur ; Stefanich, Eric ; Mai, Elaine ; Young, Judy ; Johnson, Clarissa ; Huseni, Mahrukh ; Wang, Xinhua ; Chen, Yvonne ; Wang, Peiyin ; Wang, Hong ; Dybdal, Noel ; Chu, Yu-Waye ; Chiorazzi, Nicholas ; Scheer, Justin M. ; Junttila, Teemu ; Totpal, Klara ; Dennis, Mark S. ; Ebens, Allen J.

Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell–recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B [...]

Cet article passe en revue les travaux récents mettant en évidence des mécanismes par lesquels, via le récepteur TRL4, le paclitaxel et divers médicaments anticancéreux favorisent le processus métastatique tout en réduisant la taille de la tumeur primitive

The Role of TLR4 in Chemotherapy-Driven Metastasis

Ran, Sophia

Tumor resistance to cytotoxic drugs is one of the main obstacles to successful cancer therapy. Emerging evidence suggests that chemoresistance is promoted by substances released from dead and damaged cells that activate the host repair program orchestrated by Toll-like receptor-4 (TLR4). TLR4 is often overexpressed in malignant and tumor-infiltrating immune cells. In addition to endogenous ligands released by therapy-induced tumor destruction, TLR4 is directly activated by paclitaxel, one of [...]

A partir de données portant sur 38 028 patients, puis menée in vitro, cette étude identifie des mutations dans l'exon 14 du gène MET en association avec la réponse à un inhibiteur de MET

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors

Frampton, Garrett M. ; Ali, Siraj M. ; Rosenzweig, Mark ; Chmielecki, Juliann ; Lu, Xinyuan ; Bauer, Todd M. ; Akimov, Mikhail ; Bufill, Jose ; Lee, Carrie ; Jentz, David ; Hoover, Rick ; Ou, Ignatius ; Salgia, Ravi ; Brennan, Tim ; Chalmers, Zachary ; Elvin, Julia A. ; Erlich, Rachel ; Fichtenholtz, Alex ; Gowen, Kyle A. ; Greenbowe, Joel ; Johnson, Adrienne ; Khaira, Depinder ; McMahon, Caitlin ; Sanford, Eric M. ; Roels, Steven ; White, Jared ; Lipson, Doron ; Yelensky, Roman ; Morosini, Deborah ; Ross, Jeffrey S. ; Collisson, Eric ; Peters, Malte ; Stephens, Philip J. ; Miller, Vincent A.

Focal amplification and activating point mutation of the MET gene are well characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types is unknown. Here we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), [...]

Menée à l'aide de modèles murins présentant un gène p53 muté, cette étude suggère l'intérêt du ganetespib, un inhibiteur de la protéine de choc thermique Hsp90, pour le traitement d'un cancer

Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment

Alexandrova, E. M. ; Yallowitz, A. R. ; Li, D. ; Xu, S. ; Schulz, R. ; Proia, D. A. ; Lozano, G. ; Dobbelstein, M. ; Moll, U. M.

Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities. Although currently 11 million patients worldwide live with tumours expressing highly [...]

Menée in vitro et in vivo, cette étude met en évidence l'efficacité d'une stratégie chimique à base de conjugués entre une molécule active (JQ1) et un dérivé de la thalidomide (phthalimide) permettant la dégradation sélective de protéines notoirement difficiles à cibler, par exemple la protéine BRD4 impliquée dans la croissance des cellules leucémiques

Phthalimide conjugation as a strategy for in vivo target protein degradation

Winter, Georg E. ; Buckley, Dennis L. ; Paulk, Joshiawa ; Roberts, Justin M. ; Souza, Amanda ; Dhe-Paganon, Sirano ; Bradner, James E.

The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a [...]

Menée sur des modèles animaux (souris et singes), cette étude suggère l'intérêt d'une molécule appelée MGD006, un anticorps humanisé bispécifique se liant au CD123 et au CD3 des antigènes exprimés respectivement sur les cellules leucémiques et les lymphocytes T, pour le traitement d'une leucémie myéloïde aiguë

A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: Preclinical activity and safety in nonhuman primates

Chichili, Gurunadh R. ; Huang, Ling ; Li, Hua ; Burke, Steve ; He, Leilei ; Tang, Qin ; Jin, Linda ; Gorlatov, Sergey ; Ciccarone, Valentina ; Chen, Francine ; Koenig, Scott ; Shannon, Michele ; Alderson, Ralph ; Moore, Paul A. ; Johnson, Syd ; Bonvini, Ezio

Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may benefit from targeted immunotherapy approaches. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule that binds T lymphocytes and cells expressing CD123, an antigen up-regulated in several hematological malignancies including AML. MGD006 mediates blast killing in AML samples, together with concomitant activation and expansion of residual T cells. MGD006 is designed to be [...]

Menée in vitro et in vivo, cette étude suggère l'intérêt de combiner un inhibiteur de mTOR et un inhibiteur de FAK pour le traitement d'une tumeur neuroendocrine du pancréas

Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

François, Rony A. ; Maeng, Kyungah ; Nawab, Akbar ; Kaye, Frederic J. ; Hochwald, Steven N. ; Zajac-Kaye, Maria

Background: Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling. Methods: We characterized [...]

Menée in vitro et in vivo sur des modèles de cancer du poumon, cette étude met en évidence l'activité antitumorale d'une petite molécule appelé BDA-336 qui se lie de façon sélective au domaine BH4 de Bcl2

Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy

Han, Bingshe ; Park, Dongkyoo ; Li, Rui ; Xie, Maohua ; Owonikoko, Taofeek K ; Zhang, Guojing ; Sica, Gabriel L ; Ding, Chunyong ; Zhou, Jia ; Magis, Andrew T ; Chen, Zhuo G ; Shin, Dong M ; Ramalingam, Suresh S ; Khuri, Fadlo R ; Curran, Walter J ; Deng, Xingming

The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer xenografts derived from cell lines and patient without [...]

Menée in vitro, à l'aide de xénogreffes et d'échantillons tumoraux prélevés sur 20 patients atteints d'un neuroblastome, cette étude met en évidence des mécanismes par lesquels, par leur transfert dans le micro-environnement tumoral via des exosomes, deux micro-ARNs favorisent la résistance au cisplatine

Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy

Challagundla, Kishore B. ; Wise, Petra M. ; Neviani, Paolo ; Chava, Haritha ; Murtadha, Mariam ; Xu, Tong ; Kennedy, Rebekah ; Ivan, Cristina ; Zhang, Xinna ; Vannini, Ivan ; Fanini, Francesca ; Amadori, Dino ; Calin, George A. ; Hadjidaniel, Michael ; Shimada, Hiroyuki ; Jong, Ambrose ; Seeger, Robert C. ; Asgharzadeh, Shahab ; Goldkorn, Amir ; Fabbri, Muller

Background: How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL). Methods: Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts [...]

Mené sur 10 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale du pembrolizumab

Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients With Advanced Solid Tumors

Patnaik, Amita ; Kang, Soonmo Peter ; Rasco, Drew ; Papadopoulos, Kyriakos P. ; Elassaiss-Schaap, Jeroen ; Beeram, Muralidhar ; Drengler, Ronald ; Chen, Cong ; Smith, Lon S ; Espino, Guillermo ; Gergich, Kevin ; Delgado, Liliana M. ; Daud, Adil I. ; Lindia, Jill A. ; Li, Xiaoyun Nicole ; Pierce, Robert H. ; Yearley, Jennifer H ; Wu, Dianna ; Laterza, Omar ; Lehnert, Manfred ; Iannone, Robert ; Tolcher, Anthony W.

Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. Experimental Design: In a 3+3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) until progression or intolerable toxicity. Seven additional patients received 10 mg/kg Q2W. Thirteen patients participated in a 3-week intrapatient dose escalation [...]

Mené sur 11 patients atteints d'un mélanome métastatique, cet essai de phase I évalue l'efficacité et la toxicité d'un traitement combinant sorafénib et bortézomib

A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma

Sullivan, Ryan J. ; Ibrahim, Nageatte ; Lawrence, Donald P. ; Aldridge, Julie ; Giobbie-Hurder, Anita ; Hodi, F. Stephen ; Flaherty, Keith T. ; Conley, Christine ; Mier, James W. ; Atkins, Michael B. ; McDermott, David F.

Lessons Learned : This study is a rare example of effective doses of both targeted agents being both administered and tolerated. This combination should not be used in melanoma. Background : Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. Methods : Patients with metastatic [...]

Mené sur 436 patients atteints d'un mélanome de stade IIIB ou IV, cet essai de phase III évalue l'efficacité, du point de vue du taux de réponse durable, et la toxicité d'une immunothérapie oncolytique à base d'un virus herpès simplex de type 1 par rapport à des injections sous-cutanées du facteur de croissance des granulocytes et macrophages

Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma

Andtbacka, Robert H.I. ; Kaufman, Howard L. ; Collichio, Frances ; Amatruda, Thomas ; Senzer, Neil ; Chesney, Jason ; Delman, Keith A. ; Spitler, Lynn E. ; Puzanov, Igor ; Agarwala, Sanjiv S. ; Milhem, Mohammed ; Cranmer, Lee ; Curti, Brendan ; Lewis, Karl ; Ross, Merrick ; Guthrie, Troy ; Linette, Gerald P. ; Daniels, Gregory A. ; Harrington, Kevin ; Middleton, Mark R. ; Miller, Wilson H. ; Zager, Jonathan S. ; Ye, Yining ; Yao, Bin ; Li, Ai ; Doleman, Susan ; VanderWalde, Ari ; Gansert, Jennifer ; Coffin, Robert

Purpose : Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1–derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. Patients and Methods : Patients with injectable melanoma that was not surgically resectable were [...]

Mené sur 25 patients atteints d'un myélome multiple récemment diagnostiqué ou récidivant, cet essai évalue la faisabilité et l'efficacité, du point de vue de la survie sans progression, d'une thérapie cellulaire par transfert adoptif de lymphocytes infiltrant la moelle

Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma

Noonan, Kimberly A. ; Huff, Carol A. ; Davis, Janice ; Lemas, M. Victor ; Fiorino, Susan ; Bitzan, Jeffrey ; Ferguson, Anna ; Emerling, Amy ; Luznik, Leo ; Matsui, William ; Powell, Jonathan ; Fuchs, Ephraim ; Rosner, Gary L. ; Epstein, Caroline ; Rudraraju, Lakshmi ; Ambinder, Richard F. ; Jones, Richard J. ; Pardoll, Drew ; Borrello, Ivan

Successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time. We hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. We describe the results from the first clinical trial using MILs in MM. Twenty-five patients with [...]

Mené en Chine sur 276 patients atteints d'un cancer du poumon non épidermoïde non à petites cellules de stade avancé ou métastatique, cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression, de l'ajout du bévacizumab à un traitement combinant carboplatine et paclitaxel

BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non–Small-Cell Lung Cancer

Zhou, Caicun ; Wu, Yi-Long ; Chen, Gongyan ; Liu, Xiaoqing ; Zhu, Yunzhong ; Lu, Shun ; Feng, Jifeng ; He, Jianxing ; Han, Baohui ; Wang, Jie ; Jiang, Guoliang ; Hu, Chunhong ; Zhang, Hao ; Cheng, Gang ; Song, Xiangqun ; Lu, You ; Pan, Hongming ; Zheng, Wenjuan ; Yin, Anny-Yue

Purpose : The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients and Methods : Patients age ≥ 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non–small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m2) intravenously (CP) on day 1 [...]

Cet article passe en revue les travaux récents sur les traitements d'un cancer du poumon non à petites cellules en fonction de ses caractéristiques moléculaires

Refining the treatment of NSCLC according to histological and molecular subtypes

Thomas, Anish ; Liu, Stephen V. ; Subramaniam, Deepa S. ; Giaccone, Giuseppe

In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents [...]

Mené sur 800 patients atteints d'un cancer colorectal réfractaire, cet essai international de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité d'un composé développé au Japon, le TAS-102

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Mayer, Robert J. ; Van Cutsem, Eric ; Falcone, Alfredo ; Yoshino, Takayuki ; Garcia-Carbonero, Rocio ; Mizunuma, Nobuyuki ; Yamazaki, Kentaro ; Shimada, Yasuhiro ; Tabernero, Josep ; Komatsu, Yoshito ; Sobrero, Alberto ; Boucher, Eveline ; Peeters, Marc ; Tran, Ben ; Lenz, Heinz-Josef ; Zaniboni, Alberto ; Hochster, Howard ; Cleary, James M. ; Prenen, Hans ; Benedetti, Fabio ; Mizuguchi, Hirokazu ; Makris, Lukas ; Ito, Masanobu ; Ohtsu, Atsushi

BACKGROUND : Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients. METHODS : In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall [...]

Mené sur 16 patients atteints d'un cancer colorectal métastatique présentant un gène KRAS muté, cet essai de phase I évalue la dose maximale tolérée du pimasertib, un inhibiteur de la signalisation MAPK, en combinaison avec une chimiothérapie FOLFIRI

Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer

Macarulla, T. ; Cervantes, A. ; Tabernero, J. ; Roselló, S. ; Van Cutsem, E. ; Tejpar, S. ; Prenen, H. ; Martinelli, E. ; Troiani, T. ; Laffranchi, B. ; Jego, V. ; von Richter, O. ; Ciardiello, F.

Background: The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib. Methods: Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the [...]

Cet article passe en revue les travaux récents sur l'usage de thérapies ciblées anti VEGF et d'inhibiteurs mTOR pour le traitement des patients atteints d'un carcinome rénal non à cellules claires

New molecular targets in non clear renal cell carcinoma: an overview of ongoing clinical trials

Ciccarese, Chiara ; Massari, Francesco ; Santoni, Matteo ; Heng, Daniel Y. C. ; Sotte, Valeria ; Brunelli, Matteo ; Conti, Alessandro ; Cheng, Liang ; Lopez-Beltran, Antonio ; Scarpelli, Marina ; Cascinu, Stefano ; Tortora, Giampaolo ; Montironi, Rodolfo

Non-clear cell renal cell carcinomas (nccRCCs) are a heterogeneous group of tumors, characterized by different histological features, molecular alterations, clinical outcomes, and responses to treatment. According to the 2004 WHO classification, 50 different histotypes were recognized. In 2013, five new distinct epithelial tumors and three provisional entities have been added to this classification, relying on morphology, immunohistochemistry, cytogenetics, and molecular pathology advances. [...]

A partir d'une revue systématique de la littérature, cet article fait le point sur la toxicité des inhibiteurs de tyrosine kinase en combinaison avec une radiothérapie crânienne chez les patients atteints d'un cancer du poumon non à petites cellules

Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: A systematic review

Hendriks, Lizza E. L. ; Schoenmaekers, Janna ; Zindler, Jaap D. ; Eekers, Danielle B. P. ; Hoeben, Ann ; de Ruysscher, Dirk K. M. ; Dingemans, Anne-Marie C.

Recently, non-small cell lung cancer (NSCLC) has been partly subclassified into molecularly-defined oncogene “addicted” tumors for which targeted agents are available. Tyrosine kinase inhibitors (TKI) are currently approved for patients with an activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement. In these patients, brain metastases are often the first site of progression while on TKI treatment. The TKI may however still be active on [...]

Mené sur 79 patients atteints d'un cancer rectal non métastatique de stade T3 ou T4 (durée médiane de suivi : 4 ans), cet essai de phase II évalue l'intérêt d'une radiothérapie avec modulation d'intensité dans le cadre d'une chimioradiothérapie néoadjuvante à base de capécitabine et d'oxaliplatine pour réduire la toxicité gastro-intestinale

NRG Oncology Radiation Therapy Oncology Group 0822: A phase II study of preoperative chemoradiotherapy utilizing intensity modulated radiation therapy (IMRT) in combination with capecitabine and oxaliplatin for patients with locally advanced rectal cancer

Hong, Theodore S. ; Moughan, Jennifer ; Garofalo, Michael C. ; Bendell, Johanna ; Berger, Adam C. ; Oldenburg, Nicklas B. E. ; Anne, Pramila Rani ; Perera, Francisco ; Lee, R. Jeffrey ; Jabbour, Salma K. ; Nowlan, Adam ; DeNittis, Albert ; Crane, Christopher

Purpose : To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. Materials and Methods : Patients with localized, non-metastatic T3 or T4 rectal cancer < 12 cm from the anal verge were enrolled in a prospective, multi-institutional, single arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3D-conformal [...]

Menée à partir de données portant sur 103 patients atteints d'un glioblastome primitif, cette étude coréenne évalue le bénéfice, en termes de survie, de l'ajout du lévétiracétam à un traitement combinant une chimioradiothérapie concomitante et une chimiothérapie adjuvante à base de témozolomide

Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme

Kim, Young-Hoon ; Kim, Tackeun ; Joo, Jin-Deok ; Han, Jung Ho ; Kim, Yu Jung ; Kim, In Ah ; Yun, Chang-Ho ; Kim, Chae-Yong

BACKGROUND : A chemosensitizing effect of levetiracetam (LEV) has been suggested because LEV inhibits O-6 methylguanine-DNA methyltransferase (MGMT). However, the survival benefit of LEV has not been clinically documented. The objective of this study was to assess the survival benefit of LEV compared with other antiepileptic drugs as a chemosensitizer to temozolomide for patients with glioblastoma. METHODS : In total, 103 consecutive patients with primary glioblastoma who received concomitant [...]

A partir d'une revue de la littérature (82 articles identifiés), cette étude analyse la méthodologie des essais cliniques visant à déterminer la dose maximale tolérée d'un anticorps monoclonal évalué pour la première fois chez des patients atteints d'un cancer

Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies

Tosi, Diego ; Laghzali, Yassine ; Vinches, Marie ; Alexandre, Marie ; Homicsko, Krisztian ; Fasolo, Angelica ; Del Conte, Gianluca ; Durigova, Anna ; Hayaoui, Nadia ; Gourgou, Sophie ; Gianni, Luca ; Mollevi, Caroline

Purpose : We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. Methods : We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. Results : A total of 82 publications describing FIH trials were selected for [...]