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Accueil Nota Bene Cancer V2 Numéro 125 du 28 Février 2012 Traitements

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Nota Bene Cancer Numéro 125 du 28 Février 2012 RSS

Traitements

Traitements localisés : découverte et développement

Menée sur des lignées cellulaires humaines de cancer de la prostate et sur un modèle murin, cette étude montre que le trioxyde d'arsenic augmente la sensibilité des cellules tumorales aux rayonnements ionisants, qu'elles soient dépendantes ou non aux androgènes

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    Menée sur des lignées cellulaires humaines de cancer de la prostate et sur un modèle murin, cette étude montre que le trioxyde d'arsenic augmente la sensibilité des cellules tumorales aux rayonnements ionisants, qu'elles soient dépendantes ou non aux androgènes

    “Arsenic Trioxide Enhances the Radiation Sensitivity of Androgen-Dependent and -Independent Human Prostate Cancer Cells”

    • Chiu, Hui-Wen;Chen, Yi-An;Ho, Sheng-Yow;Wang, Ying-Jan

    Prostate cancer is the most common malignancy in men. In the present study, LNCaP (androgen-sensitive human prostate cancer cells) and PC-3 cells (androgen-independent human prostate cancer cells) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) and to determine the underlying mechanisms in vitro and in vivo. We found that IR combined with ATO increases the therapeutic efficacy compared to individual treatments in LNCaP and PC-3 human prostate cancer cells. In addition, combined treatment showed enhanced reactive oxygen species (ROS) generation compared to treatment with ATO or IR alone in PC-3 cells. Combined treatment induced autophagy and apoptosis in LNCaP cells, and mainly induced autophagy in PC-3 cells. The cell death that was induced by the combined treatment was primarily the result of inhibition of the Akt/mTOR signaling pathways. Furthermore, we found that the combined treatment of cells pre-treated with 3-MA ...


Mots clés : Prostate; Traitements (Traitements localisés : découverte et développement)

Menée in vitro sur des cellules cancéreuses du foie, cette étude identifie le mécanisme par lequel des anticorps conjugués à des nanoparticules d'or pénètrent sélectivement dans les cellules tumorales avant d'être soumises à un champ électrique externe

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    Menée in vitro sur des cellules cancéreuses du foie, cette étude identifie le mécanisme par lequel des anticorps conjugués à des nanoparticules d'or pénètrent sélectivement dans les cellules tumorales avant d'être soumises à un champ électrique externe

    “Stability of antibody-conjugated gold nanoparticles in the endo-lysosomal nanoenvironment : Implications for non-invasive radiofrequency-based cancer therapy”

    • Raoof, Mustafa;Corr, Stuart J.;Kaluarachchi, Warna D.;Massey, Katheryn L.;Briggs, Katrina;Zhu, Cihui;Cheney, Matthew A.;Wilson, Lon J.;Curley, Steven A.

    The use of non-invasive radiofrequency (RF) electric fields as an energy source for thermal activation of nanoparticles within cancer cells could be a valuable addition to the emerging field of nano-mediated cancer therapies. Based on investigations of cell death through hyperthermia, and offering the ability for total body penetration by RF fields, this technique is thought to compliment and possibly out-perform existing nano-heat-treatments that utilize alternative heat production via optical or magnetic stimuli. However, it remains a challenge to understand fully the complex RF-nanoparticle-intracellular interactions before full system optimization can be engineered. Herein we have shown that liver cancer cells can selectively internalize antibody-conjugated gold nanoparticles (AuNPs) through receptor-mediated endocytosis, with the nanoparticles predominantly accumulating and aggregating within cytoplasmic endo-lysosomes. After exposure to an external RF field, non-aggregated AuNPs ...


Mots clés : Foie; Traitements (Traitements localisés : découverte et développement)

Traitements localisés : applications cliniques

Mené en Grande-Bretagne, Belgique, Afrique du Sud et aux Pays-Bas sur 868 patientes atteintes d'un cancer du sein de stade I / II (durée médiane de suivi : 22,1 ans), cet essai randomisé de phase III compare l'efficacité d'un traitement conservateur du sein et d'une mastectomie radicale modifiée, du point de vue de l'incidence cumulée de métastases distantes et du taux de survie globale à 20 ans

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    Mené en Grande-Bretagne, Belgique, Afrique du Sud et aux Pays-Bas sur 868 patientes atteintes d'un cancer du sein de stade I / II (durée médiane de suivi : 22,1 ans), cet essai randomisé de phase III compare l'efficacité d'un traitement conservateur du sein et d'une mastectomie radicale modifiée, du point de vue de l'incidence cumulée de métastases distantes et du taux de survie globale à 20 ans

    “Breast conserving therapy versus mastectomy for stage I?II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial”

    • Litière, Saskia;Werutsky, Gustavo;Fentiman, Ian S.;Rutgers, Emiel;Christiaens, Marie-Rose;Van Limbergen, Erik;Baaijens, Margreet H. A.;Bogaerts, Jan;Bartelink, Harry

    The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. The EORTC 10801trialwas open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. After a median follow-up of 22·1 years (IQR 18·5?23·8), 175 patients (42%) had distant ...


  • Long-term outcome of breast conserving therapy
    The Lancet Oncology, sous presse, 2012 (commentaire)
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    Mené en Grande-Bretagne, Belgique, Afrique du Sud et aux Pays-Bas sur 868 patientes atteintes d'un cancer du sein de stade I / II (durée médiane de suivi : 22,1 ans), cet essai randomisé de phase III compare l'efficacité d'un traitement conservateur du sein et d'une mastectomie radicale modifiée, du point de vue de l'incidence cumulée de métastases distantes et du taux de survie globale à 20 ans

    “Long-term outcome of breast conserving therapy”

    • Benson, John R.


Mots clés : Sein; Traitements (Traitements localisés : applications cliniques)

Traitements systémiques : découverte et développement

Mené sur 46 patients atteints d'un cancer non résécable des voies biliaires ne présentant pas de mutations du gène KRAS, cet essai de phase II évalue, du point de vue de la survie sans progression, le panitumumab en combinaison avec la gemcitabine et l'oxaliplatine

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    Mené sur 46 patients atteints d'un cancer non résécable des voies biliaires ne présentant pas de mutations du gène KRAS, cet essai de phase II évalue, du point de vue de la survie sans progression, le panitumumab en combinaison avec la gemcitabine et l'oxaliplatine

    “Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer”

    • Jensen, L. H.;Lindebjerg, J.;Ploen, J.;Hansen, T. F.;Jakobsen, A.

    Background: Combination chemotherapy has proven beneficial in biliary tract cancer and further improvements may be achieved by individualizing treatment based on biomarkers and by adding biological agents. We report the effect of chemotherapy with panitumumab as first-line therapy for KRAS wild-type irresectable biliary tract cancer.Patients and methods: Patients were treated with gemcitabine 1000 mg/m2, oxaliplatin 60 mg/m2, and panitumumab 6 mg/kg i.v. every 2 weeks followed by two daily administrations of capecitabine 1000 mg/m2 in 7 days.Results: During 22 months, 46 patients were included in a single institution. The primary end point, fraction of progression-free survival (PFS) at 6 months, was 31/42 [74%; 95% confidence interval (CI) 58% to 84%]. Forty-two patients had measurable disease. Response rate was 33% and disease control rate 86%. Median PFS was 8.3 months (95% CI 6.7–8.7 months) and median overall survival was 10.0 months (95% CI 7.4–12.7 months). Toxicity was ...


Mots clés : Voies biliaires; Traitements (Traitements systémiques : découverte et développement)

Mené sur 31 patientes atteintes d'un cancer avancé du sein surexprimant EpCAM, cet essai de phase IB évalue l'activité antitumorale et la toxicité d'un traitement combinant docétaxel et adecatumumab, un anticorps ciblé sur la molécule d'adhérence cellulaire EpCAM

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    Mené sur 31 patientes atteintes d'un cancer avancé du sein surexprimant EpCAM, cet essai de phase IB évalue l'activité antitumorale et la toxicité d'un traitement combinant docétaxel et adecatumumab, un anticorps ciblé sur la molécule d'adhérence cellulaire EpCAM

    “Phase IB study of the EpCAM antibody adecatumumab combined with docetaxel in patients with EpCAM-positive relapsed or refractory advanced-stage breast cancer”

    • Schmidt, M.;Rüttinger, D.;Sebastian, M.;Hanusch, C. A.;Marschner, N.;Baeuerle, P. A.;Wolf, A.;Göppel, G.;Oruzio, D.;Schlimok, G.;Steger, G. G.;Wolf, C.;Eiermann, W.;Lang, A.;Schuler, M.

    Background: Targeted therapy options in HER2-negative breast cancer are limited. This open-label, multicenter phase IB dose-escalation trial was conducted to determine safety, tolerability, and antitumor activity of a combination of docetaxel (Taxotere) and increasing doses of adecatumumab, a human IgG1 antibody targeting epithelial cell adhesion molecule (EpCAM), in EpCAM-positive relapsed or primary refractory advanced-stage breast cancer.Patients and methods: Patients pretreated with up to four prior chemotherapy regimens received increasing adecatumumab doses either every 3 weeks (q3w) or weekly (qw) combined with docetaxel (100 mg/m2 q3w). Primary end points were safety and tolerability. Antitumor activity was evaluated according to RECIST. Clinical benefit was defined as complete or partial response or stable disease for ≥24 weeks.Results: Thirty-one evaluable patients were treated. Most adverse events were mild to moderate in severity. Neutropenia, leukocytopenia, ...


Mots clés : Sein; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et in vivo, cette étude évalue l'activité d'un traitement combinant le panobinostat, qui inhibe des histones déacétylases, et la chloroquine, qui inhibe l'autophagie, sur des cellules de cancer du sein triplement négatif

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    Menée in vitro et in vivo, cette étude évalue l'activité d'un traitement combinant le panobinostat, qui inhibe des histones déacétylases, et la chloroquine, qui inhibe l'autophagie, sur des cellules de cancer du sein triplement négatif

    “Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells”

    • Rao, Rekha;Balusu, Ramesh;Fiskus, Warren;Mudunuru, Uma;Venkannagari, Sreedhar;Chauhan, Lata;Smith, Jacqueline E.;Hembruff, Stacey L;Ha, Kyungsoo;Atadja, Peter W;Bhalla, Kapil N

    Histone deacetylase (HDAC) inhibitors (HDIs) induce endoplasmic reticulum (ER) stress and apoptosis, while promoting autophagy, which promotes cancer cell survival when apoptosis is compromised. Here, we determined the in vitro and in vivo activity of the combination of the pan-HDI panobinostat (PS) and the autophagy inhibitor chloroquine (CL) against human estrogen/progesterone receptor and HER2 (triple)-negative breast cancer (TNBC) cells. Treatment of MB-231 and SUM159PT cells with PS disrupted the hsp90/histone deacetylase 6/HSF1/p97 complex, resulting in the upregulation of heat shock proteins. This was accompanied by the induction of enhanced autophagic flux as evidence by increased expression of LC3B-II and the degradation of the autophagic substrate p62. Treatment with PS also induced the accumulation and co-localization of p62 with LC3B-II in cytosolic foci as evidenced by immunofluorescent confocal microscopy. Inhibition of PS-induced autophagic flux by CL markedly induced ...


Mots clés : Sein; Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les perspectives offertes par les nouvelles stratégies d'immunothérapie dans le cancer du poumon non à petites cellules

  • Vaccines in non-small cell lung cancer: Rationale, combination strategies and update on clinical trials
    Critical Reviews in Oncology/Hematology, sous presse, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par les nouvelles stratégies d'immunothérapie dans le cancer du poumon non à petites cellules

    “Vaccines in non-small cell lung cancer: Rationale, combination strategies and update on clinical trials”

    • De Pas, Tommaso;Giovannini, Monica;Rescigno, Maria;Catania, Chiara;Toffalorio, Francesca;Spitaleri, Gianluca;Delmonte, Angelo;Barberis, Massimo;Spaggiari, Lorenzo;Solli, Piergiorgio;Veronesi, Giulia;De Braud, Filippo

    Non-small cell lung cancer (NSCLC) remains the leading cause of cancer related mortality worldwide and despite some advances in therapy the overall prognosis remains disappointing. New therapeutic approaches like vaccination have been proposed and several clinical trials are ongoing. Many tumor antigens have been identified so far and specific tumor vaccines targeting these antigens have been developed. Even if the ideal setting for vaccine therapy might be the adjuvant one, vaccines seem to be potentially beneficial also in advanced disease and combination therapy could be a promising treatment option. In the advanced setting anti-MUC-1 vaccine (belagenpumatucel) and anti-TGF-β2 vaccine (BPL-25) have entered in phase III trials as maintenance therapy after first line chemotherapy. In the adjuvant setting the most relevant and promising vaccines are directed against MAGE-A3 and PRAME, respectively. We will review the key points for effective active immunotherapies and combination ...


Mots clés : Poumon; Traitements (Traitements systémiques : découverte et développement)

Menée sur des modèles murins de tumeurs neuroendocrines du pancréas, cette étude montre que, si un inhibiteur de VEGF favorise les processus invasif et métastatique, cet effet peut être annihilé par un inhibiteur de la voie c-Met (crizotinib ou cabozantinib)

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    Menée sur des modèles murins de tumeurs neuroendocrines du pancréas, cette étude montre que, si un inhibiteur de VEGF favorise les processus invasif et métastatique, cet effet peut être annihilé par un inhibiteur de la voie c-Met (crizotinib ou cabozantinib)

    “Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors”

    • Sennino, Barbara;Ishiguro-Oonuma, Toshina;Wei, Ying;Naylor, Ryan M.;Williamson, Casey W.;Bhagwandin, Vikash;Tabruyn, Sebastien P.;You, Weon-Kyoo;Chapman, Harold A.;Christensen, James G.;Aftab, Dana T.;McDonald, Donald M.

    Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling ...


Mots clés : Pancréas; Traitements (Traitements systémiques : découverte et développement)

Mené sur 16 patients dans la phase I et 31 patients dans la phase II, cet essai évalue l'efficacité, du point de vue de la réponse objective, et la toxicité d'une combinaison "cetuximab, everolimus et capécitabine" pour le traitement d'un cancer avancé du pancréas

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    Mené sur 16 patients dans la phase I et 31 patients dans la phase II, cet essai évalue l'efficacité, du point de vue de la réponse objective, et la toxicité d'une combinaison "cetuximab, everolimus et capécitabine" pour le traitement d'un cancer avancé du pancréas

    “A phase I/II, non-randomized, feasibility/safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with advanced pancreatic cancer”

    • Kordes, Sil;Richel, Dick;Klümpen, Heinz-Josef;Weterman, Mariëtte;Stevens, Arnoldus;Wilmink, Johanna

    Background Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine. Methods Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5–10 mg/day) and capecitabine (600–800 mg/m 2 bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response. Results Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot ...


Mots clés : Pancréas; Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les travaux récents sur le développement de nouvelles thérapies ciblées et d'immunothérapies dans le myélome multiple

  • Latest advances and current challenges in the treatment of multiple myeloma
    Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le développement de nouvelles thérapies ciblées et d'immunothérapies dans le myélome multiple

    “Latest advances and current challenges in the treatment of multiple myeloma”

    • Mahindra, Anuj;Laubach, Jacob;Raje, Noopur;Munshi, Nikhil;Richardson, Paul G.;Anderson, Kenneth

    Effectively treating patients with multiple myeloma is challenging. The development of therapeutic regimens over the past decade that incorporate the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has been the cornerstone of improving the outcome of patients with myeloma. Although these treatment regimens have improved patient survival, nearly all patients eventually relapse. Our improved understanding of the biology of the disease and the importance of the microenvironment has translated into ongoing work to help overcome the challenge of relapse. Several classes of agents including next-generation proteasome inhibitors, immunomodulatory agents, selective histone-deacetylase inhibitors, antibody and antitumor immunotherapy approaches are currently undergoing preclinical and clinical evaluation. This Review provides an update on the latest advances in the treatment of multiple myeloma. In particular, we focus on novel therapies including ...


Mots clés : Myélome multiple et maladies immunoprolifératives; Traitements (Traitements systémiques : découverte et développement)

A partir de greffes, sur des souris, d'échantillons tumoraux prélevés sur 34 patients atteints d'un mélanome métastatique, cette étude évalue l'efficacité d'un composé appelé RAF265 et identifie des facteurs associés à la réponse au traitement

  • RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
    Clinical Cancer Research, sous presse, 2012 (résumé)
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    A partir de greffes, sur des souris, d'échantillons tumoraux prélevés sur 34 patients atteints d'un mélanome métastatique, cette étude évalue l'efficacité d'un composé appelé RAF265 et identifie des facteurs associés à la réponse au traitement

    “RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors”

    • Su, Yingjun;Vilgelm, Anna E.;Kelley, Mark C;Hawkins, Oriana;Liu, Yan;Boyd, Kelli L;Kantrow, Sara;Splittgerber, Ryan;Short, Sarah P;Sobolik-Delmaire, Tammy;Zaja-Milatovic, Snjezana;Dahlman, Kimberly B;Amiri, Katayoun I;Jiang, Aixiang;Lu, Pengcheng;Shyr, Yu;Stuart, Darrin;Levy, Shawn E;Sosman, Jeffrey A.;Richmond, Ann

    Purpose:The purpose of this pre-clinical study was to determine the effectiveness of RAF265, a multi-kinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response. Experimental Design:Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17/34) were evaluated for response to RAF265 (40 mg/kg, QD) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, MEK/ERK phosphorylation, proliferation, and apoptosis markers were evaluated. Results:Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAFV600E/K), while 8 of 17 (47%) were BRAF wild-type (BRAFWT). Tumor implants from 7/17 patients (41%) responded to RAF265 treatment with >50% reduction in tumor growth. Five of the 7 (71%) responders were BRAFWT, of which one carried c-KIT L576P and another ...


Mots clés : Mélanome; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et in vivo, cette étude évalue l'intérêt d'un composé appelé XL888, un inhibiteur de HSP90, en cas d'apparition d'une résistance au vemurafenib dans le traitement d'un mélanome

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    Menée in vitro et in vivo, cette étude évalue l'intérêt d'un composé appelé XL888, un inhibiteur de HSP90, en cas d'apparition d'une résistance au vemurafenib dans le traitement d'un mélanome

    “The heat shock protein-90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms”

    • Paraiso, Kim H.T.;Haarberg, Eirik;Wood, Elizabeth;Rebecca, Vito W;Chen, Y. Ann;Xiang, Yun;Ribas, Antoni;Lo, Roger S.;Weber, Jeffrey S.;Sondak, Vernon K.;John, Jobin;Sarnaik, Amod A;Koomen, John;Smalley, Keiran S.M.

    Purpose: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study demonstrates the potential therapeutic utility of the HSP90 inhibitor (XL888) in 6 different models of vemurafenib resistance. Experimental design: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was demonstrated in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts and melanoma biopsies. Mechanistic studies were performed to determine the mechanism of XL888-induced apoptosis. Results: XL888 potently inhibited cell growth, induced apoptosis and prevented the growth of vemurafenib resistant melanoma cell lines in 3D cell culture, long-term colony formation assays and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the ...


Mots clés : Mélanome; Traitements (Traitements systémiques : découverte et développement)

Menée sur 13 patients atteints d'un mélanome présentant la mutation BRAF(V600E), cette étude évalue les effets d'un composé appelé GSK2118436 ou dabrafenib, un inhibiteur spécifique de BRAF(V600E), sur le système immunitaire

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    Menée sur 13 patients atteints d'un mélanome présentant la mutation BRAF(V600E), cette étude évalue les effets d'un composé appelé GSK2118436 ou dabrafenib, un inhibiteur spécifique de BRAF(V600E), sur le système immunitaire

    “BRAF(V600) Inhibitor GSK2118436 Targeted Inhibition of Mutant BRAF in Cancer Patients Does Not Impair Overall Immune Competency”

    • Hong, David S.;Vence, Luis M.;Falchook, Gerald S;Radvanyi, Laszlo G.;Liu, Chengwen;Goodman, Vicki L;Legos, Jeffrey J;Blackman, Samuel C;Scamardo, Antonio T;Kurzrock, Razelle;Lizee, Gregory;Hwu, Patrick

    PURPOSE: An intact immune system likely contributes to the outcome of treatment, and may be important for clearance of drug-resistant tumor cells and for prevention of recurrence. While pharmacologic inhibition of BRAF(V600E) in melanoma patients, which is linked to immune suppression, results in an initial response rate, these responses are typically of limited duration. Combining immunotherapeutic drugs with kinase-targeted agents is an attractive strategy to increase clinical efficacy. Evidence suggesting that MAPK pathway activation in tumor cells contributes to immune suppression, suggests that the two approaches may be synergistic, provided that BRAF(V600E) inhibitors are nontoxic to immune cells. METHODS: To assess effects of mutant BRAF inhibition on systemic immunity, we studied 13 patients with tumors carrying a BRAF mutation who underwent treatment with GSK2118436, a V600 mutant BRAF-specific inhibitor. We performed peripheral blood immunomonitoring prior to and following ...


Mots clés : Mélanome; Traitements (Traitements systémiques : découverte et développement)

Mené sur 28 patients atteints d'une leucémie à tricholeucocytes et ayant développé une résistance à la chimiothérapie, cet essai de phase I évalue l'activité et la toxicité d'une immunotoxine recombinante, le moxetumomab pasudotox

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    Mené sur 28 patients atteints d'une leucémie à tricholeucocytes et ayant développé une résistance à la chimiothérapie, cet essai de phase I évalue l'activité et la toxicité d'une immunotoxine recombinante, le moxetumomab pasudotox

    “Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia”

    • Kreitman, Robert J.;Tallman, Martin S.;Robak, Tadeusz;Coutre, Steven;Wilson, Wyndham H.;Stetler-Stevenson, Maryalice;FitzGerald, David J.;Lechleider, Robert;Pastan, Ira

    Purpose To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL).Patients and Methods Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies.Results Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 μg/kg, four patients at 40 μg/kg, and 12 patients at 50 μg/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and ...


  • Targeted Immunotherapy for Hairy Cell Leukemia
    Journal of Clinical Oncology, sous presse, 2012 (commentaire)
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    Mené sur 28 patients atteints d'une leucémie à tricholeucocytes et ayant développé une résistance à la chimiothérapie, cet essai de phase I évalue l'activité et la toxicité d'une immunotoxine recombinante, le moxetumomab pasudotox

    “Targeted Immunotherapy for Hairy Cell Leukemia”

    • Park, Jae H. ; Levine, Ross L.


Mots clés : Leucémie; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et in vivo, cette étude évalue l'activité et la toxicité d'une nouvelle fluoropyrimidine, FdUMP[10], pour le traitement d'une leucémie myéloïde aiguë

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    Menée in vitro et in vivo, cette étude évalue l'activité et la toxicité d'une nouvelle fluoropyrimidine, FdUMP[10], pour le traitement d'une leucémie myéloïde aiguë

    “Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity”

    • Pardee, Timothy S.;Gomes, Evan;Jennings-Gee, Jamie;Caudell, David;Gmeiner, William H.

    Acute Myeloid Leukemia is an aggressive malignancy that leads to marrow failure and death. There is a desperate need for new therapies. The novel fluoropyrimidine, FdUMP[10], was highly active against both human AML cell lines, (IC50 values 3.4 - 21.5 nM) and murine lines (IC50 values 123.8 to 131.4 pM). In all cases, the IC50 of FdUMP[10] was lower than for cytarabine and ~1000 times lower than 5-fluorouracil (5-FU). FdUMP[10] remained effective against cells expressing the Flt3 ITD, BCR-ABL, MN1 and an shRNA against p53. It had activity against patient samples at concentrations that did not impact normal hematopoietic cells. FdUMP[10] inhibited thymidylate synthase (TS) and trapped topoisomerase I cleavage complexes (Top1CC) leading to DNA damage and apoptosis. All cell lines and nearly all primary AML samples examined expressed both TS and Top1. In vivo, FdUMP[10] was active against a syngeneic AML model with a survival advantage equivalent to doxorubicin plus cytarabine. 5-FU ...


Mots clés : Leucémie; Traitements (Traitements systémiques : découverte et développement)

Menée sur 12 patients atteints d'une leucémie myéloïde aiguë présentant une duplication interne en tandem du gène FLT3 , puis poursuivie à l'aide de xénogreffes, cette étude montre que des cellules initiatrices de leucémie acquièrent une résistance au sorafenib grâce à des mutations D835

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    Menée sur 12 patients atteints d'une leucémie myéloïde aiguë présentant une duplication interne en tandem du gène FLT3 , puis poursuivie à l'aide de xénogreffes, cette étude montre que des cellules initiatrices de leucémie acquièrent une résistance au sorafenib grâce à des mutations D835

    “Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non-responsiveness associated with a D835 mutation”

    • Man, Cheuk Him;Fung, Tsz Kan;Ho, Christa;Han, Heron HC;Chow, Howard CH;Ma, Alvin CH;Choi, William WL;Lok, Si;Cheung, Alice MS;Eaves, Connie;Kwong, Yok Lam;Leung, Anskar YH

    Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% acute myeloid leukemias (AML) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD+ AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow (BM) myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells which have become sorafenib resistant expressed a number of genes including ALDH1A1, JAK3 and MMP15, whose functions were unknown in AML. NOD/SCID mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain (TKD) mutations at D835 were identified in leukemia initiating ...


Mots clés : Leucémie; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro, cette étude analyse les effets d'un composé appelé ON 01910.Na ou rigosertib, un inhibiteur de PI3K, sur des cellules de leucémie lymphocytaire chronique

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    Menée in vitro, cette étude analyse les effets d'un composé appelé ON 01910.Na ou rigosertib, un inhibiteur de PI3K, sur des cellules de leucémie lymphocytaire chronique

    “ON 01910.Na is selectively cytotoxic for Chronic Lymphocytic Leukemia cells through a dual mechanism involving PI3K/AKT inhibition and induction of oxidative stress”

    • Chapman, Colby M;Sun, Xiameng;Roschewski, Mark;Aue, Georg;Farooqui, Mohamed;Stennett, Lawrence S;Gibellini, Federica;Arthur, Diane;Perez-Galan, Patricia;Wiestner, Adrian

    Purpose: Chronic Lymphocytic Leukemia (CLL), a malignancy of mature B-cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation, and may confer chemotherapy resistance. ON 01910.Na (Rigosertib) a multikinase PI3K inhibitor is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology. Experimental design: Cytotoxicity of ON 01910.Na against CLL cells from 34 patients was determined in vitro using flow cytometry of cells stained with Annexin V and CD19. Global gene expression profiling on Affymetrix microarrays, flow cytometry, western blotting, and co-cultures with stroma cells were used to delineate ON 01910.Na mechanism of action. Results: ON 01910.Na induced apoptosis in CLL B-cells without significant toxicity against T-cells or normal B-cells. ON 01910.Na was equally active ...


Mots clés : Leucémie; Traitements (Traitements systémiques : découverte et développement)

Mené sur 66 patients âgés atteints d'un cancer colorectal avancé, cet essai évalue, du point de vue de la survie sans progression, un traitement combinant cetuximab et capécitabine en fonction de la présence ou de l'absence d'une mutation du gène KRAS

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    Mené sur 66 patients âgés atteints d'un cancer colorectal avancé, cet essai évalue, du point de vue de la survie sans progression, un traitement combinant cetuximab et capécitabine en fonction de la présence ou de l'absence d'une mutation du gène KRAS

    “First-Line Cetuximab Plus Capecitabine in Elderly Patients with Advanced Colorectal Cancer: Clinical Outcome and Subgroup Analysis According to KRAS Status from a Spanish TTD Group Study”

    • Sastre, Javier;Grávalos, Cristina;Rivera, Fernando;Massuti, Bartomeu;Valladares-Ayerbes, Manuel;Marcuello, Eugenio;Manzano, José L.;Benavides, Manuel;Hidalgo, Manuel;Díaz-Rubio, Eduardo;Aranda, Enrique

    Abstract Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab–capecitabine combination has not previously been tested in elderly patients with advanced CRC.Material and Methods. Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.v. infusion followed by 250 mg/m2 i.v. weekly plus capecitabine at a dose of 1,250 mg/m2 every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m2 every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine.Results. The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%–67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%–39.7%). The median progression-free survival (PFS) ...


Mots clés : Colon-rectum; Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les travaux récents sur le développement d'inhibiteurs de la voie de signalisation Interleukine-6/Jak/Stat pour le traitement des cancers

  • Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies
    Journal of Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le développement d'inhibiteurs de la voie de signalisation Interleukine-6/Jak/Stat pour le traitement des cancers

    “Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies”

    • Sansone, Pasquale;Bromberg, Jacqueline

    The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Menée in vitro, cette étude identifie la présence de la protéine MRP-1, associée à une multirésistance thérapeutique, dans des mitochondries de cellules normales et de cellules cancéreuses

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    Menée in vitro, cette étude identifie la présence de la protéine MRP-1, associée à une multirésistance thérapeutique, dans des mitochondries de cellules normales et de cellules cancéreuses

    “Detection and characterisation of multi-drug resistance protein 1 (MRP-1) in human mitochondria”

    • Roundhill, E. A.;Burchill, S. A.

    Background: Overexpression of plasma membrane multi-drug resistance protein 1 (MRP-1) can lead to multidrug resistance. In this study, we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues. Methods: MRP-1 expression and subcellular localisation in normal and cancer cells and tissues was examined by differential centrifugation and western blotting, and immunofluorescence microscopy. Viable mitochondria were isolated and MRP-1 efflux activity measured using the calcein-AM functional assay. MRP-1 expression was increased using retroviral infection and specific overexpression confirmed by RNA array. Cell viability was determined by trypan blue exclusion and annexin V-propidium iodide labelling of cells. Results: MRP-1 was detected in the mitochondria of cancer and normal cells and tissues. The efflux activity of mitochondrial MRP-1 was more efficient (55–64%) than that of plasma membrane MRP-1 (11–22%; P<0.001). ...


Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Traitements systémiques : applications cliniques

Cet article analyse la controverse sur l'intérêt d'une chimiothérapie adjuvante pour les patientes atteintes d'un cancer du sein de type luminal A

  • Is Adjuvant Chemotherapy Useful for Women With Luminal A Breast Cancer?
    Journal of Clinical Oncology, sous presse, 2012 (article en libre accès)
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    Cet article analyse la controverse sur l'intérêt d'une chimiothérapie adjuvante pour les patientes atteintes d'un cancer du sein de type luminal A

    “Is Adjuvant Chemotherapy Useful for Women With Luminal A Breast Cancer?”

    • Coates, Alan S.;Colleoni, Marco;Goldhirsch, Aron

    Cytotoxic chemotherapy is, on average, beneficial in delaying relapse and prolonging survival for women with early breast cancer. Thus, there is a motivation to prescribe it freely to all or nearly all such women. Guidelines from the 2000 National Institutes of Health Consensus Development Conference stated that “because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status”and that “at the present time, there are no convincing data to support the use of any known biologic factor in selecting a specific adjuvant chemotherapy regimen in breast cancer.” (...)


Mots clés : Sein; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur l'évaluation de l'ipilimumab pour le traitement d'un cancer du poumon non à petites cellules

  • Ipilimumab: its potential in non-small cell lung cancer
    Therapeutic Advances in Medical Oncology, Vol. 4 (2), pp. 43-50, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur l'évaluation de l'ipilimumab pour le traitement d'un cancer du poumon non à petites cellules

    “Ipilimumab: its potential in non-small cell lung cancer”

    • Tomasini, Pascale;Khobta, Nataliya;Greillier, Laurent;Barlesi, Fabrice

    Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, ...


Mots clés : Poumon; Traitements (Traitements systémiques : applications cliniques)

Mené sur 132 patients atteints d'un mélanome métastatique présentant la mutation BRAF V600, cet essai de phase II évalue, du point de vue du taux de réponse globale et de la survie globale, l'efficacité du vemurafenib (durée médiane de suivi : 12,9 mois)

  • Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib
    New England Journal of Medicine, Vol. 366 (8), pp. 707-714, 2012 (résumé)
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    Mené sur 132 patients atteints d'un mélanome métastatique présentant la mutation BRAF V600, cet essai de phase II évalue, du point de vue du taux de réponse globale et de la survie globale, l'efficacité du vemurafenib (durée médiane de suivi : 12,9 mois)

    “Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib”

    • Sosman, Jeffrey A.;Kim, Kevin B.;Schuchter, Lynn;Gonzalez, Rene;Pavlick, Anna C.;Weber, Jeffrey S.;McArthur, Grant A.;Hutson, Thomas E.;Moschos, Stergios J.;Flaherty, Keith T.;Hersey, Peter;Kefford, Richard;Lawrence, Donald;Puzanov, Igor;Lewis, Karl D.;Amaravadi, Ravi K.;Chmielowski, Bartosz;Lawrence, H. Jeffrey;Shyr, Yu;Ye, Fei;Li, Jiang;Nolop, Keith B.;Lee, Richard J.;Joe, Andrew K.;Ribas, Antoni

    Background: Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. Methods: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. Results: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a ...


Mots clés : Mélanome; Traitements (Traitements systémiques : applications cliniques)

Mené sur 241 patients atteints d'une tumeur stromale gastro-intestinale de stade avancé, cet essai de phase III évalue, du point de vue de la survie sans progression, l'efficacité du nilotinib après échec d'un traitement à l'imatinib et au sunitinib

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    Mené sur 241 patients atteints d'une tumeur stromale gastro-intestinale de stade avancé, cet essai de phase III évalue, du point de vue de la survie sans progression, l'efficacité du nilotinib après échec d'un traitement à l'imatinib et au sunitinib

    “Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib”

    • Reichardt, P.;Blay, J.-Y.;Gelderblom, H.;Schlemmer, M.;Demetri, G. D.;Bui-Nguyen, B.;McArthur, G. A.;Yazji, S.;Hsu, Y.;Galetic, I.;Rutkowski, P.

    Background: This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure.Patients and methods: Patients were randomized 2 : 1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC + imatinib, or BSC + sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib.Results: Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P = 0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P = 0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P = 0.29). Post hoc subset analyses in patients with progression and only ...


Mots clés : Appareil digestif (autre); Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents, en particulier les essais de phase III, dans le traitement des tumeurs neuroendocrines

  • A New Era for the Systemic Therapy of Neuroendocrine Tumors
    The Oncologist, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents, en particulier les essais de phase III, dans le traitement des tumeurs neuroendocrines

    “A New Era for the Systemic Therapy of Neuroendocrine Tumors”

    • Eads, Jennifer R.;Meropol, Neal J.

    Abstract Carcinoids and pancreatic neuroendocrine tumors are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease. An improved understanding of the molecular mechanisms involved in these tumors has implicated several pathways that have led to new therapeutic approaches. In this manuscript, we describe the biology of neuroendocrine tumors and approaches to systemic therapy. We review early data regarding the use of cytotoxics and several recent studies employing more targeted approaches that promise to change the standard of care. Specifically, phase III studies indicate that pharmacologic inhibition of the vascular endothelial growth factor pathway with sunitinib, and of the mammalian target of rapamycin pathway with everolimus, appears to have altered the natural history of these diseases. These successes set the stage for further advances in the management of patients with neuroendocrine tumors.


Mots clés : Cancer (général); Traitements (Traitements systémiques : applications cliniques)

Combinaison de traitements localisés et systémiques

Menée sur 636 patients atteints d'un cancer de la prostate présentant un risque intermédiaire de récidive, cette étude montre qu'un traitement anti-androgénique de courte durée, combiné à une radiothérapie avec protocole d'escalade de dose, améliore la survie sans échec des patients

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    Menée sur 636 patients atteints d'un cancer de la prostate présentant un risque intermédiaire de récidive, cette étude montre qu'un traitement anti-androgénique de courte durée, combiné à une radiothérapie avec protocole d'escalade de dose, améliore la survie sans échec des patients

    “Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer”

    • Bian, S. X.;Kuban, D. A.;Levy, L. B.;Oh, J.;Castle, K. O.;Pugh, T. J.;Choi, S.;McGuire, S. E.;Nguyen, Q. N.;Frank, S. J.;Nguyen, P. L.;Lee, A. K.;Hoffman, K. E.

    Background: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain.Patients and methods: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan–Meier and log-rank tests compared failure-free survival (FFS) with and without ADT.Results: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve ...


Mots clés : Prostate; Traitements (Combinaison de traitements localisés et systémiques)

Menée sur 38 patients atteints d'un adénocarcinome du poumon localement avancé et non résécable, cette étude multicentrique évalue la faisabilité d'une chimiothérapie d'induction par cisplatine-vinorelbine suivie d'un traitement combinant le gefitinib avec une radiothérapie thoracique concomitante

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    Menée sur 38 patients atteints d'un adénocarcinome du poumon localement avancé et non résécable, cette étude multicentrique évalue la faisabilité d'une chimiothérapie d'induction par cisplatine-vinorelbine suivie d'un traitement combinant le gefitinib avec une radiothérapie thoracique concomitante

    “Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402)”

    • Niho, S.;Ohe, Y.;Ishikura, S.;Atagi, S.;Yokoyama, A.;Ichinose, Y.;Okamoto, H.;Takeda, K.;Shibata, T.;Tamura, T.;Saijo, N.;Fukuoka, M.

    Background: We conducted a feasibility study of induction chemotherapy followed by gefitinib and thoracic radiotherapy (TRT) for unresectable locally advanced adenocarcinoma of the lung.Patients and methods: Patients received induction chemotherapy with cisplatin (80 mg/m2, days 1 and 22) and vinorelbine (25 mg/m2, days 1, 8, 22, and 29) followed by gefitinib (250 mg daily, beginning on day 43, for 1 year) and TRT (60 Gy/30 fractions, days 57–98). The primary end point was feasibility, which was defined as the proportion of patients who completed 60 Gy of TRT and received >75% of the planned dose of gefitinib without developing grade 2 or worse pneumonitis.Results: Of the 38 enrolled patients, 23 patients [60.5%; 80% confidence interval (CI) 48.8–71.3] completed treatment without experiencing grade 2 or worse pneumonitis. During the chemoradiation phase, grade 3–4 alanine aminotransferase elevations were observed in 37.1% of the patients. The overall response rate was 73.0%. The ...


Mots clés : Poumon; Traitements (Combinaison de traitements localisés et systémiques)

A partir des données de 24 études incluant 1 271 patients atteints d'un cancer du rectum à haut risque de récidive et résécable, cette étude évalue l'intérêt d'une chimiothérapie néoadjuvante, combinée ou non à une chimioradiothérapie préopératoire, du point de vue de la réponse pathologique complète, de la survie sans récidive et de la survie globale des patients

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    A partir des données de 24 études incluant 1 271 patients atteints d'un cancer du rectum à haut risque de récidive et résécable, cette étude évalue l'intérêt d'une chimiothérapie néoadjuvante, combinée ou non à une chimioradiothérapie préopératoire, du point de vue de la réponse pathologique complète, de la survie sans récidive et de la survie globale des patients

    “Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation ?”

    • Glynne-Jones, R.;Anyamene, N.;Moran, B.;Harrison, M.

    Background: For patients with resectable rectal cancer chemoradiation (CRT) or short-course preoperative radiotherapy (SCPRT) reduces locoregional failure, without extending disease-free survival (DFS) or overall survival (OS). Compliance to postoperative adjuvant chemotherapy is poor. Neoadjuvant chemotherapy (NACT) offers an alternative strategy. Methods : A systematic computerised database search identified studies exploring NACT alone or NACT preceding/succeeding radiation. The primary outcome measure was pathological complete response (pCR). Secondary outcome measures included acute toxicity, surgical morbidity, circumferential resection margin, locoregional failure, DFS and OS. Results : Four case reports, 12 phase I/II studies, 4 randomised phase II and one randomised phase III study evaluated chemotherapy before CRT. Four prospective studies reviewed chemotherapy after CRT. Three phase II studies investigated chemotherapy using FOLFOX plus bevacizumab without radiotherapy. In ...


Mots clés : Colon-rectum; Traitements (Combinaison de traitements localisés et systémiques)

Mené sur 263 patientes ayant subi un traitement chirurgical pour un cancer du col de l'utérus à haut risque de récidive et de stade IB–IIB, cet essai de phase III compare l'efficacité d'une chimioradiothérapie séquentielle par paclitaxel-carboplatine et d'une chimioradiothérapie concomitante à base de cisplatine

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    Mené sur 263 patientes ayant subi un traitement chirurgical pour un cancer du col de l'utérus à haut risque de récidive et de stade IB–IIB, cet essai de phase III compare l'efficacité d'une chimioradiothérapie séquentielle par paclitaxel-carboplatine et d'une chimioradiothérapie concomitante à base de cisplatine

    “A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study”

    • Sehouli, J.;Runnebaum, I. B.;Fotopoulou, C.;Blohmer, U.;Belau, A.;Leber, H.;Hanker, L. C.;Hartmann, W.;Richter, R.;Keyver-Paik, M. D.;Oberhoff, C.;Heinrich, G.;duBois, A.;Olbrich, C.;Simon, E.;Friese, K.;Kimmig, R.;Boehmer, D.;Lichtenegger, W.;Kuemmel, S.

    Background: Simultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity.Patients and methods: An open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m2) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m2/week) (arm-B) in patients with stage IB–IIB CC after surgery. Primary objective was progression-free survival (PFS).Results: Overall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4–89.1] in arm-B versus 87.2% (95% CI 81.2–93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = ...


Mots clés : Col de l'utérus; Traitements (Combinaison de traitements localisés et systémiques)

Ressources et infrastructures (Traitements)

A partir de données portant sur 2 182 patients inclus dans des essais de phase I entre 2005 et 2007 dans 14 hôpitaux européens, cette étude évalue l'association entre deux modèles, basés sur divers facteurs mesurés à l'entrée dans l'essai, et le risque de décès à 90 jours

  • Patient Selection for Oncology Phase I Trials: A Multi-Institutional Study of Prognostic Factors
    Journal of Clinical Oncology, sous presse, 2012 (résumé)
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    A partir de données portant sur 2 182 patients inclus dans des essais de phase I entre 2005 et 2007 dans 14 hôpitaux européens, cette étude évalue l'association entre deux modèles, basés sur divers facteurs mesurés à l'entrée dans l'essai, et le risque de décès à 90 jours

    “Patient Selection for Oncology Phase I Trials: A Multi-Institutional Study of Prognostic Factors”

    • Olmos, David;A'Hern, Roger P.;Marsoni, Silvia;Morales, Rafael;Gomez-Roca, Carlos;Verweij, Jaap;Voest, Emile E.;Schöffski, Patrick;Ang, Joo Ern;Penel, Nicolas;Schellens, Jan H.;del Conte, Gianluca;Brunetto, Andre T.;Evans, T.R. Jeffry;Wilson, Richard;Gallerani, Elisa;Plummer, Ruth;Tabernero, Josep;Soria, Jean-Charles;Kaye, Stan B.

    Purpose The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials.Patients and Methods Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis.Results The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical ...


Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

Cet article passe en revue les obstacles réglementaires s'opposant au développement de médicaments anticancéreux accompagnés d'un biomarqueur prédictif de la réponse thérapeutique

  • Hurdles in anticancer drug development from a regulatory perspective
    Nature Reviews Clinical Oncology, sous presse, 2012 (résumé)
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    Cet article passe en revue les obstacles réglementaires s'opposant au développement de médicaments anticancéreux accompagnés d'un biomarqueur prédictif de la réponse thérapeutique

    “Hurdles in anticancer drug development from a regulatory perspective”

    • Jonsson, Bertil;Bergh, Jonas

    Between January 2001 and January 2012, 48 new medicinal products for cancer treatment were licensed within the EU, and 77 new indications were granted for products already licensed. In some cases, a major improvement to existing therapies was achieved, for example, trastuzumab in breast cancer. In other cases, new fields for effective drug therapy opened up, such as in chronic myeloid leukemia, and renal-cell carcinoma. In most cases, however, the benefit–risk balance was considered to be only borderline favorable. Based on our assessment of advice procedures for marketing authorization, 'need for speed' seems to be the guiding principle in anticancer drug development. Although, for drugs that make a difference, early licensure is of obvious importance to patients, this is less evident in the case of borderline drugs. Without proper incentives and with hurdles inside and outside companies, a change in drug development cannot be expected; drugs improving benefit–risk modestly over ...


Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

Cet article propose de nouvelles méthodes d'utilisation des droits de propriété intellectuelle visant à faciliter les collaborations en recherche translationnelle

  • Recalibrating Intellectual Property Rights to Enhance Translational Research Collaborations
    Science Translational Medicine, Vol. 4 (122), pp. 122cm3, 2012 (résumé)
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    Cet article propose de nouvelles méthodes d'utilisation des droits de propriété intellectuelle visant à faciliter les collaborations en recherche translationnelle

    “Recalibrating Intellectual Property Rights to Enhance Translational Research Collaborations”

    • Bubela, Tania;FitzGerald, Garret A.;Gold, E. Richard

    Multisectoral collaborative models for drug and therapeutic research and development (R&D) are emerging, requiring a recalibration of how intellectual property rights (IPRs) are used. Although these models appear promising, little study has been conducted on the optimal blend of sharing and exclusion as mediated through the proactive use or nonuse of IPRs. This Commentary is a call for a combination of theoretical and empirical analyses to build a comprehensive understanding of the interplay between formal IP laws, institutions that administer and manage IPRs, and the use of IPRs in practice to better construct and manage collaborations. Such analyses require outcome metrics formulated to measure the success of therapeutic outcomes and to capture the complexity of a highly networked R&D environment.


Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))

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