Traitements

Menée sur une cohorte multicentrique comportant 609 patientes de type caucasien ou africain et atteintes d'un carcinome canalaire in situ traité par chirurgie conservatrice du sein et par radiothérapie (durée médiane de suivi : 5,2 ans), cette étude analyse les caractéristiques cliniques et pathologiques des patientes ainsi que la réponse aux traitements en fonction de leur appartenance ethnique

• Multi-Institutional Experience of Ductal Carcinoma In Situ in Black vs White Patients Treated With Breast-Conserving Surgery and Whole Breast Radiation Therapy
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur une cohorte multicentrique comportant 609 patientes de type caucasien ou africain et atteintes d'un carcinome canalaire in situ traité par chirurgie conservatrice du sein et par radiothérapie (durée médiane de suivi : 5,2 ans), cette étude analyse les caractéristiques cliniques et pathologiques des patientes ainsi que la réponse aux traitements en fonction de leur appartenance ethnique

  “Multi-Institutional Experience of Ductal Carcinoma In Situ in Black vs White Patients Treated With Breast-Conserving Surgery and Whole Breast Radiation Therapy”

  • Nelson, Carl;Bai, Harrison;Neboori, Hanmanth;Takita, Cristiane;Motwani, Sabin;Wright, Jean L.;Hobeika, Georges;Haffty, Bruce G.;Jones, Tiffanie;Goyal, Sharad;Moran, Meena S.

  Given the paucity of data on racial disparities in ductal carcinoma in situ (DCIS), the data from a multi-institutional cohort of DCIS patients treated with breast-conserving surgery and whole breast radiation therapy (RT) were analyzed to determine whether racial disparities or differences exist. A total of 533 white and 76 black DCIS patients from 3 university-based cancer centers were uniformly treated with breast-conserving surgery and RT. All patient data were collected and analyzed as a function of race. The median follow-up was 5.2 years. No significant racial differences were seen in tumor size, age at diagnosis, estrogen receptor status, necrosis, or grade (all P>.05). Of the treatment parameters, the RT dose delivered, boost, positive margin rates, frequency of hormone receptor status assessment, and receipt of hormonal therapy for the 2 cohorts did not significantly differ (all P>.05). The local relapse-free survival was similar at 5 years (96.1% and 98.1%, P=.399) and 10 ...

  
  

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

A partir d'une revue systématique de la littérature publiée jusqu'en février 2012 (2 essais, 25 études rétrospectives et 1 094 cas), cette méta-analyse compare l'efficacité, la toxicité et les avantages de deux techniques de néphrectomie, l'une utilisant la laparo-endoscopie avec accès unique et l'autre la laparoscopie conventionnelle

• Laparoendoscopic Single-Site Nephrectomy Compared with Conventional Laparoscopic Nephrectomy: A Systematic Review and Meta-analysis of Comparative Studies
  • European urology, sous presse, 2012 (résumé)
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  A partir d'une revue systématique de la littérature publiée jusqu'en février 2012 (2 essais, 25 études rétrospectives et 1 094 cas), cette méta-analyse compare l'efficacité, la toxicité et les avantages de deux techniques de néphrectomie, l'une utilisant la laparo-endoscopie avec accès unique et l'autre la laparoscopie conventionnelle

  “Laparoendoscopic Single-Site Nephrectomy Compared with Conventional Laparoscopic Nephrectomy: A Systematic Review and Meta-analysis of Comparative Studies”

  • Xinxiang, Fan;Tianxin, Lin;Kewei, Xu;Zi, Yin;Hai, Huang;Wen, Dong;Jian, Huang

  Context : Laparoendoscopic single-site (LESS) surgery has increasingly been used to perform radical, partial, simple, or donor nephrectomy to reduce the morbidity and scarring associated with surgical intervention. Studies comparing LESS nephrectomy (LESS-N) and conventional laparoscopic nephrectomy (CL-N) have reported conflicting results. Objective :To assess the current evidence regarding the efficiency, safety, and potential advantages of LESS-N compared with CL-N. Evidence acquisition : We comprehensively searched PubMed, Embase, and the Cochrane Library and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective comparative studies assessing the two techniques. Evidence synthesis : Two RCTs and 25 retrospective studies including a total of 1094 cases were identified. Although LESS-N was associated with a longer operative time (weighted mean difference [WMD]: 9.87 min; 95% confidence interval [CI], 3.37–16.38; p = ...

  
  

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

Menée sur 340 patients atteints d'un cancer du rein de stade T1, cette étude rétrospective monocentrique compare les résultats oncologiques et fonctionnels à 5 ans d'une néphrectomie par laparoscopie et d'une néphrectomie partielle par voie ouverte

• Laparoscopic vs open partial nephrectomy for T1 renal tumours: evaluation of long-term oncological and functional outcomes in 340 patients
  • BJU International, sous presse, 2012 (résumé)
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  Menée sur 340 patients atteints d'un cancer du rein de stade T1, cette étude rétrospective monocentrique compare les résultats oncologiques et fonctionnels à 5 ans d'une néphrectomie par laparoscopie et d'une néphrectomie partielle par voie ouverte

  “Laparoscopic vs open partial nephrectomy for T1 renal tumours: evaluation of long-term oncological and functional outcomes in 340 patients”

  • Springer, Christopher;Hoda, M. Raschid;Fajkovic, Harun;Pini, Giovannalberto;Mohammed, Nasreldin;Fornara, Paolo;Greco, Francesco

  Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?Whereas open nerve-sparing surgery (NSS) represents the ‘gold standard’ in the surgical therapy of T1 renal tumours, with the advances in laparoscopic surgery, the refinement of intracorporeal suturing and the availability of haemosealant substances, the laparoscopic approach to NSS is increasingly used. Laparoscopic partial nephrectomy (LPN), however, is currently performed in just a few high-volume reference centres, and its diffusion has been limited by the steep learning curve. Conversely, robot-assisted LPN is emerging as a promising procedure, able to tackle the technical difficulties of LPN and leading to a broader diffusion of minimally invasive treatment of small renal masses.Our study provides long-term follow-up outcomes concerning surgical and oncological outcomes and a detailed evaluation of the renal function in patients affected by T1 renal cancers who ...

  
  

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

Mené sur 113 patients atteints d'un cancer de la prostate de stade T1 à T3N0M0, cet essai multicentrique de phase II évalue la toxicité gastro-intestinale et génito-urinaire d'une radiothérapie hypofractionnée à haute dose puis analyse les résultats biochimiques et cliniques associés au traitement

• Hypofractionated High-Dose Radiation Therapy for Prostate Cancer: Long-Term Results of a Multi-Institutional Phase II Trial
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Mené sur 113 patients atteints d'un cancer de la prostate de stade T1 à T3N0M0, cet essai multicentrique de phase II évalue la toxicité gastro-intestinale et génito-urinaire d'une radiothérapie hypofractionnée à haute dose puis analyse les résultats biochimiques et cliniques associés au traitement

  “Hypofractionated High-Dose Radiation Therapy for Prostate Cancer: Long-Term Results of a Multi-Institutional Phase II Trial”

  • Fonteyne, Valérie;Soete, Guy;Arcangeli, Stefano;De Neve, Wilfried;Rappe, Bernard;Storme, Guy;Strigari, Lidia;Arcangeli, Giorgio;De Meerleer, Gert

  To report late gastrointestinal (GI) and genitourinary (GU) toxicity, biochemical and clinical outcomes, and overall survival after hypofractionated radiation therapy for prostate cancer (PC). Three institutions included 113 patients with T1 to T3N0M0 PC in a phase II study. Patients were treated with 56 Gy in 16 fractions over 4 weeks. Late toxicity was scored using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria extended with additional symptoms. Biochemical outcome was reported according to the Phoenix definition for biochemical failure. The incidence of late GI and GU toxicity was low. The 3-year actuarial risk of developing late GU and GI toxicity of grade ≥2 was 13% and 8% respectively. Five-year biochemical non-evidence of disease (bNED) was 94%. Risk group, T stage, and deviation from planned hormone treatment were significant predictive factors for bNED. Deviation from hormone treatment remained significant in ...

  
  

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

A partir d'une revue systématique de la littérature publiée entre janvier 2000 et décembre 2011 (31 études, 6 453 cas), cette étude évalue, du point de vue de la survie sans maladie, l'efficacité et les effets indésirables des ultrasons focalisés de haute intensité pour traiter un cancer de la prostate

• High-intensity focused ultrasound (HIFU) for definitive treatment of prostate cancer
  • BJU International, sous presse, 2012 (résumé)
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  A partir d'une revue systématique de la littérature publiée entre janvier 2000 et décembre 2011 (31 études, 6 453 cas), cette étude évalue, du point de vue de la survie sans maladie, l'efficacité et les effets indésirables des ultrasons focalisés de haute intensité pour traiter un cancer de la prostate

  “High-intensity focused ultrasound (HIFU) for definitive treatment of prostate cancer”

  • Cordeiro, Ernesto R.;Cathelineau, Xavier;Thüroff, Stefan;Marberger, Michael;Crouzet, Sebastien;de la Rosette, Jean J. M. C. H.

  What's known on the subject? and What does the study add?Novel therapeutic methods have emerged in recent years as ‘focal’ treatment alternatives in which cancer foci can be eradicated and greatly reducing the associated side-effects of radical treatment. High-intensity focused ultrasound (HIFU) seems to result in a well fitted technology, which has proven short- to medium-term cancer control, with a low rate of complications comparable with those of established therapies.This is an up-to-date review of the available literature on HIFU as a definitive treatment of prostate cancer. It describes the technique in a comprehensive approach in terms of technical features, procedure, indications, and gives an overview of its historical background; finally, we present the future applications of HIFU and its development trend. OBJECTIVES * •To provide an up-to-date review of the available literature on high-intensity focused ultrasound (HIFU) as a definitive treatment of prostate cancer. ...

  
  

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

Menée sur une cohorte de 1 845 patients atteints d'un cancer de la prostate traité entre 1999 et 2007 (durée médiane de suivi : 5 ans), cette étude monocentrique évalue, du point de vue de la récidive biochimique à 5 ans et du taux d'incontinence urinaire post-opératoire, les résultats oncologiques et fonctionnels à long terme d'une prostatectomie radicale par voie laparoscopique

• Long-term oncological and continence outcomes after laparoscopic radical prostatectomy: a single-centre experience
  • BJU International, sous presse, 2012 (résumé)
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  Menée sur une cohorte de 1 845 patients atteints d'un cancer de la prostate traité entre 1999 et 2007 (durée médiane de suivi : 5 ans), cette étude monocentrique évalue, du point de vue de la récidive biochimique à 5 ans et du taux d'incontinence urinaire post-opératoire, les résultats oncologiques et fonctionnels à long terme d'une prostatectomie radicale par voie laparoscopique

  “Long-term oncological and continence outcomes after laparoscopic radical prostatectomy: a single-centre experience”

  • Busch, Jonas;Stephan, Carsten;Herold, Anja;Erber, Barbara;Kempkensteffen, Carsten;Hinz, Stefan;Lein, Michael;Weikert, Steffen;Miller, Kurt;Magheli, Ahmed

  Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?Over the past decade, minimally invasive laparoscopic radical prostatectomy and more recently robot-assisted laparoscopic prostatectomy have been introduced and have proven equally effective compared with open surgery in terms of mid-term cancer control and complication rates. Because long-term data is lacking, open prostatectomy is still considered the ‘gold standard’ by some authors, who argue that minimally invasive approaches have to measure up to the excellent long-term results of open surgery.This study represents one of the largest series (1845 patients) of minimally invasive radical prostatectomy with extended follow-up (11.3 years) and detailed data on oncological outcome and postoperative incontinence. It therefore supplies previously lacking information on these details for minimally invasive prostate surgery and provides important information for patient ...

  
  

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

Menée entre 2007 et 2010 sur 118 patients atteints d'un cancer du poumon non à petites cellules (âge : 46 à 80 ans ; durée médiane de suivi : 16,6 mois), cette étude rétrospective évalue le taux de récidive cérébrale, la morbidité et la survie des patients après une irradiation cérébrale prophylactique puis analyse l'efficacité de stéroïdes pour réduire la toxicité aiguë du traitement

• Prophylactic cranial irradiation in patients with small cell lung cancer. A retrospective study of recurrence, survival and morbidity
  • Lung Cancer, sous presse, 2012 (résumé)
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  Menée entre 2007 et 2010 sur 118 patients atteints d'un cancer du poumon non à petites cellules (âge : 46 à 80 ans ; durée médiane de suivi : 16,6 mois), cette étude rétrospective évalue le taux de récidive cérébrale, la morbidité et la survie des patients après une irradiation cérébrale prophylactique puis analyse l'efficacité de stéroïdes pour réduire la toxicité aiguë du traitement

  “Prophylactic cranial irradiation in patients with small cell lung cancer. A retrospective study of recurrence, survival and morbidity”

  • Ramlov, A.;Tietze, A.;Khalil, A. A.;Knap, M. M.

  Background Prophylactic cerebral irradiation (PCI) is a standard treatment for all small cell lung cancer (SCLC) patients with response to chemotherapy. The aims of this study were: to evaluate patients undergoing PCI with regard to cerebral recurrence rate, site of recurrence, and overall survival (OS) and to investigate the influence of steroid dose on acute toxicity. Materials and methods From 2007 to 2010 a total of 118 consecutive patients underwent PCI (25 Gray in 10 fractions). In total, 114/118 received full PCI dose, all 118 were included in the study. Data were analyzed retrospectively with regard to disease stage, treatment, date of PCI, steroid dose during PCI, toxicity, time to recurrence, site of recurrence and time of death. The median follow up time was 16.6 months (range 3–54 months). Results Of the 118 patients undergoing PCI, 74 had limited disease (LD-SCLC) and 44 had extensive disease (ED-SCLC). The median age was 65 years (range ...

  
  

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

Menée sur 37 patients atteints d'un cancer métastatique et présentant des lésions pulmonaires suspectes, cette étude prospective compare l'efficacité de deux techniques de métastasectomie pulmonaire : l'une par thoracotomie assistée par vidéo et l'autre par voie ouverte

• Thoracoscopic versus open pulmonary metastasectomy: a prospective, sequentially controlled study
  • Chest, sous presse, 2012 (résumé)
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  Menée sur 37 patients atteints d'un cancer métastatique et présentant des lésions pulmonaires suspectes, cette étude prospective compare l'efficacité de deux techniques de métastasectomie pulmonaire : l'une par thoracotomie assistée par vidéo et l'autre par voie ouverte

  “Thoracoscopic versus open pulmonary metastasectomy: a prospective, sequentially controlled study”

  • Eckardt, Jens;Licht, Peter B.

  BACKGROUND: Patients with limited metastatic disease in the lung may benefit from metastasectomy. Thoracotomy is considered gold standard and video-assisted thoracoscopic surgery (VATS) is controversial because non-imaged nodules may be missed when bimanual palpation is restricted. Against guideline recommendations metastasectomy with therapeutic intent is now performed by VATS in 40% of thoracic surgeons surveyed. The evidence base for optimal surgical approach is limited to case-series and registries and no comparative surgical studies were observer-blinded.METHODS: Patients considered eligible for pulmonary metastasectomy by VATS prospectively underwent high-definition VATS by one surgical team followed by immediate thoracotomy with bimanual palpation and resection of all palpable nodules by a second surgical team during the same anaesthesia. Both surgical teams were blinded during preoperative evaluation of CT-scans and during surgery. Primary endpoints were number and histology ...

  
  

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

Menée sur 347 patients atteints d'un lymphome hodgkinien réfractaire ou récidivant et ayant reçu, sans succès, une greffe autologue de cellules souches entre 1986 et 2006, cette étude évalue, du point de vue de la survie globale à 5 ans et du contrôle local de la maladie, l'efficacité d'une radiothérapie de sauvetage (durée médiane de suivi : 31,3 mois)

• Role of Salvage Radiation Therapy for Patients With Relapsed or Refractory Hodgkin Lymphoma Who Failed Autologous Stem Cell Transplant
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Menée sur 347 patients atteints d'un lymphome hodgkinien réfractaire ou récidivant et ayant reçu, sans succès, une greffe autologue de cellules souches entre 1986 et 2006, cette étude évalue, du point de vue de la survie globale à 5 ans et du contrôle local de la maladie, l'efficacité d'une radiothérapie de sauvetage (durée médiane de suivi : 31,3 mois)

  “Role of Salvage Radiation Therapy for Patients With Relapsed or Refractory Hodgkin Lymphoma Who Failed Autologous Stem Cell Transplant”

  • Goda, Jayant S.;Massey, Christine;Kuruvilla, John;Gospodarowicz, Mary K.;Wells, Woodrow;Hodgson, David C.;Sun, Alexander;Keating, Armand;Crump, Michael;Tsang, Richard W.

  To analyze, through chart review, the efficacy of salvage radiation therapy (sRT) for relapsed or progressive Hodgkin lymphoma (HL) patients who failed autologous stem cell transplant (ASCT). Among 347 patients with recurrent/refractory HL who received ASCT from 1986-2006, 163 had post-ASCT progression or relapse. Of these, 56 received sRT and form the basis of this report. Median age at sRT was 30 years (range, 17-59 years). Disease was confined to lymph nodes in 27 patients, whereas 24 had both nodal and extranodal disease. Salvage radiation therapy alone was given in 34 patients (61%), and sRT plus chemotherapy was given in 22 (39%). Median interval from ASCT to sRT was 0.8 years (range, 0.1-5.6 years). The median dose was 35 Gy (range, 8-40.3 Gy). The sRT technique was extended-field in 14 patients (25%) and involved-field in 42 (75%). The median follow-up from sRT was 31.3 months (range, 0.2-205.5 months). Overall response rate was 84% (complete response: 36%; partial response: ...

  
  

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

A partir d'une revue de la littérature publiée jusqu'en novembre 2011 (20 études et 1 105 patients), cette méta-analyse évalue, du point de vue de la survie globale à 5 ans, de la mortalité et de la morbidité post-opératoires, l'intérêt d'une résection transthoracique pour traiter un cancer de la jonction gastro-œsophagienne

• Transthoracic Resection versus Non-Transthoracic Resection for Gastroesophageal Junction Cancer: A Meta-Analysis
  • PLoS ONE, Vol. 7 (6), pp. e37698, 2012 (article en libre accès)
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  A partir d'une revue de la littérature publiée jusqu'en novembre 2011 (20 études et 1 105 patients), cette méta-analyse évalue, du point de vue de la survie globale à 5 ans, de la mortalité et de la morbidité post-opératoires, l'intérêt d'une résection transthoracique pour traiter un cancer de la jonction gastro-œsophagienne

  “Transthoracic Resection versus Non-Transthoracic Resection for Gastroesophageal Junction Cancer: A Meta-Analysis”

  • Yang, Kun;Chen, Hai-Ning;Chen, Xin-Zu;Lu, Qing-Chun;Pan, Lin;Liu, Jie;Dai, Bin;Zhang, Bo;Chen, Zhi-Xin;Chen, Jia-Ping;Hu, Jian-Kun

  Background : The aim of this meta-analysis is to evaluate the impact of transthoracic resection on long-term survival of patients with GEJ cancer and to compare the postoperative morbidity and mortality of patients undergoing transthoracic resection with those of patients who were not undergoing transthoracic resection. Method : Searches of electronic databases identifying studies from Medline, Cochrane Library trials register, and WHO Trial Registration etc were performed. Outcome measures were survival, postoperative morbidity and mortality, and operation related events. Results :Twelve studies (including 5 RCTs and 7 non-RCTs) comprising 1105 patients were included in this meta-analysis, with 591 patients assigned treatment with transthoracic resection. Transthoracic resection did not increase the 5-y overall survival rate for RCTs and non-RCTs (HR = 1.01, 95% CI 0.80- 1.29 and HR = 0.89, 95% CI 0.70- 1.14, respectively). Stratified by the Siewert classification, our result showed ...

  
  

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

Menée à l'aide d'un modèle murin, cette étude évalue l’intérêt d'instillations répétées du bacille de Calmette-Guérin pour améliorer une immunothérapie intravésicale dans le cancer de la vessie

• Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer
  • Science Translational Medicine, Vol. 4 (137), pp. 137ra72, 2012 (résumé)
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  Menée à l'aide d'un modèle murin, cette étude évalue l’intérêt d'instillations répétées du bacille de Calmette-Guérin pour améliorer une immunothérapie intravésicale dans le cancer de la vessie

  “Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer”

  • Biot, Claire;Rentsch, Cyrill A.;Gsponer, Joel R.;Birkhäuser, Frédéric D.;Jusforgues-Saklani, Hélène;Lemaître, Fabrice;Auriau, Charlotte;Bachmann, Alexander;Bousso, Philippe;Demangel, Caroline;Peduto, Lucie;Thalmann, George N.;Albert, Matthew L.

  Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non–muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ–producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure ...

  
  

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

Menée à l'aide de xénogreffes de carcinome à cellules rénales, cette étude évalue, par comparaison avec le sunitinib et le sirolimus, l'activité du dovitinib

• A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma
  • Science Translational Medicine, Vol. 4 (137), pp. 137ra75, 2012 (résumé)
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  Menée à l'aide de xénogreffes de carcinome à cellules rénales, cette étude évalue, par comparaison avec le sunitinib et le sirolimus, l'activité du dovitinib

  “A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma”

  • Sivanand, Sharanya;Peña-Llopis, Samuel;Zhao, Hong;Kucejova, Blanka;Spence, Patrick;Pavia-Jimenez, Andrea;Yamasaki, Toshinari;McBride, David J.;Gillen, Jessica;Wolff, Nicholas C.;Morlock, Lorraine;Lotan, Yair;Raj, Ganesh V.;Sagalowsky, Arthur;Margulis, Vitaly;Cadeddu, Jeffrey A.;Ross, Mark T.;Bentley, David R.;Kabbani, Wareef;Xie, Xian-Jin;Kapur, Payal;Williams, Noelle S.;Brugarolas, James

  Most anticancer drugs entering clinical trials fail to achieve approval from the U.S. Food and Drug Administration. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidneys of mice without additives or disaggregation. Tumors from 35 of these patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at higher frequency than those from primary tumors, and stable engraftment of primary tumors in mice correlated with decreased patient survival. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and more than 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing ...

  
  

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

Mené sur 52 patients atteints d'un lymphome à cellules du manteau réfractaire ou récidivant, cet essai de phase I/II évalue un traitement combinant lénalidomide et rituximab

• Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené sur 52 patients atteints d'un lymphome à cellules du manteau réfractaire ou récidivant, cet essai de phase I/II évalue un traitement combinant lénalidomide et rituximab

  “Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial”

  • Wang, Michael;Fayad, Luis;Wagner-Bartak, Nicolaus;Zhang, Liang;Hagemeister, Fredrick;Neelapu, Sattva S.;Samaniego, Felipe;McLaughlin, Peter;Fanale, Michelle;Younes, Anas;Cabanillas, Fernando;Fowler, Nathan;Newberry, Kate J.;Sun, Luhong;Young, Ken H.;Champlin, Richard;Kwak, Larry;Feng, Lei;Badillo, Maria;Bejarano, Maria;Hartig, Kimberly;Chen, Wendy;Chen, Yiming;Byrne, Catriona;Bell, Neda;Zeldis, Jerome;Romaguera, Jorge

  The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1?21 of each 28-day cycle. 375 mg/m2intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until ...

  
  
• Beyond targeting malignant B cells
  • The Lancet Oncology, sous presse, 2012 (commentaire)
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  Mené sur 52 patients atteints d'un lymphome à cellules du manteau réfractaire ou récidivant, cet essai de phase I/II évalue un traitement combinant lénalidomide et rituximab

  “Beyond targeting malignant B cells”

  • Ansell, Stephen M.

  The anticipated overall survival for mantle-cell lymphoma (MCL) has significantly improved over the past 30 years; however, it is still only in the range of 4—5 years. 1 Patients with MCL commonly respond to initial treatment but a persistent pattern of relapse usually follows and chemoresistance commonly develops over time. A few highly selected patients have had favourable long-term disease-free survival after allogeneic stem-cell transplantation, but for most patients there is no curative treat ...

  
  

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

Menée sur un modèle murin de lymphome, cette étude évalue les effets d'un traitement à base de nanoparticules sur l'expression d'un micro-ARN oncogénique, miR-155

• Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée sur un modèle murin de lymphome, cette étude évalue les effets d'un traitement à base de nanoparticules sur l'expression d'un micro-ARN oncogénique, miR-155

  “Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma”

  • Babar, Imran A.;Cheng, Christopher J.;Booth, Carmen J.;Liang, Xianping;Weidhaas, Joanne B.;Saltzman, W. Mark;Slack, Frank J.

  MicroRNA-155 (miR-155) is an oncogenic microRNA that regulates several pathways involved in cell division and immunoregulation. It is overexpressed in numerous cancers, is often correlated with poor prognosis, and is thus a key target for future therapies. In this work we show that overexpression of miR-155 in lymphoid tissues results in disseminated lymphoma characterized by a clonal, transplantable pre-B-cell population of neoplastic lymphocytes. Withdrawal of miR-155 in mice with established disease results in rapid regression of lymphadenopathy, in part because of apoptosis of the malignant lymphocytes, demonstrating that these tumors are dependent on miR-155 expression. We show that systemic delivery of antisense peptide nucleic acids encapsulated in unique polymer nanoparticles inhibits miR-155 and slows the growth of these “addicted” pre-B-cell tumors in vivo, suggesting a promising therapeutic option for lymphoma/leukemia.

  
  

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

Menée in vitro et in vivo sur un modèle murin de leucémie myéloïde aiguë, cette étude évalue l'activité d'un composé appelé KPT-276, un nouvel inhibiteur du récepteur nucléaire CRM1

• Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia
  • Blood, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo sur un modèle murin de leucémie myéloïde aiguë, cette étude évalue l'activité d'un composé appelé KPT-276, un nouvel inhibiteur du récepteur nucléaire CRM1

  “Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia”

  • Ranganathan, Parvathi;Yu, Xueyan;Na, Caroline;Santhanam, Ramasamy;Shacham, Sharon;Kauffman, Michael;Walker, Alison;Klisovic, Rebecca;Blum, William;Caligiuri, Michael;Croce, Carlo M.;Marcucci, Guido;Garzon, Ramiro

  CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors [e.g. p53 and nucleophosmin] whose function is altered in cancer due to increased expression and overactive transport. Blocking CRM1 mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here, we investigated the anti-leukemic activity of KPT-SINE (KPT-185 and -276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent anti-proliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5 fold increase), cell-cycle arrest and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild type cell lines was observed. ...

  
  

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

Menée in vitro, cette étude met en évidence un mécanisme rendant compte de l'activité du sorafenib dans le traitement d'une tumeur stromale gastrointestinale ayant développé une résistance à l'imatinib et au sunitinib

• Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée in vitro, cette étude met en évidence un mécanisme rendant compte de l'activité du sorafenib dans le traitement d'une tumeur stromale gastrointestinale ayant développé une résistance à l'imatinib et au sunitinib

  “Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors”

  • Heinrich, Michael C;Marino-Enriquez, Adrian;Presnell, Ajia;Donsky, Rachel S.;Griffith, Diana J;McKinley, Arin;Patterson, Janice;Taguchi, Takahiro;Liang, Cher-Wei;Fletcher, Jonathan A

  Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant GI stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFRs) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against 4 GIST cell lines, 3 of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistance mutations in exons encoding the ATP/drug binding pocket, and in exons encoding the activation ...

  
  

Mots clés : Appareil digestif (autre); Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et in vivo, cette étude identifie, à l'aide d'une plateforme mettant en oeuvre des cellules souches pluripotentes humaines, une molécule qui, dotée de propriétés antipsychotiques connues, cible préférentiellement les cellules souches leucémiques

• Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells
  • Cell, Vol. 149 (6), pp. 1284-1297, 2012 (article en libre accès)
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  Menée in vitro et in vivo, cette étude identifie, à l'aide d'une plateforme mettant en oeuvre des cellules souches pluripotentes humaines, une molécule qui, dotée de propriétés antipsychotiques connues, cible préférentiellement les cellules souches leucémiques

  “Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells”

  • Sachlos, Eleftherios;Risueño, Ruth M;Laronde, Sarah;Shapovalova, Zoya;Lee, Jong-Hee;Russell, Jennifer;Malig, Monika;McNicol, Jamie D;Fiebig-Comyn, Aline;Graham, Monica;Levadoux-Martin, Marilyne;Lee, Jung Bok;Giacomelli, Andrew O;Hassell, John A;Fischer-Russell, Daniela;Trus, Michael R;Foley, Ronan;Leber, Brian;Xenocostas, Anargyros;Brown, Eric D;Collins, Tony J;Bhatia, Mickie

  Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use ...

  
  
• Target Practice: Modeling Tumors with Stem Cells
  • Cell, Vol. 149 (6), pp. 1185-1187, 2012 (commentaire)
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  Menée in vitro et in vivo, cette étude identifie, à l'aide d'une plateforme mettant en oeuvre des cellules souches pluripotentes humaines, une molécule qui, dotée de propriétés antipsychotiques connues, cible préférentiellement les cellules souches leucémiques

  “Target Practice: Modeling Tumors with Stem Cells”

  • Liu, Kai ; Ding, Sheng

  A variant neoplastic line of human pluripotent stem cell (hPSC) displays unique tumorigenic properties, including enhanced self-renewal and survival, and aberrant blockade in differentiation. Sachlos et al. adopted a neoplastic hPSC differentiation platform to screen small molecules that selectively induce differentiation of cancer stem cells.

  
  

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

Menée sur des lignées cellulaires de divers types de cancer, cette étude évalue l'intérêt d'ajouter au cisplatine un composé "donneur d'électron", appelé TMPD, pour surmonter l'apparition d'une résistance thérapeutique

• Electron transfer-based combination therapy of cisplatin with tetramethyl-p-phenylenediamine for ovarian, cervical, and lung cancers
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée sur des lignées cellulaires de divers types de cancer, cette étude évalue l'intérêt d'ajouter au cisplatine un composé "donneur d'électron", appelé TMPD, pour surmonter l'apparition d'une résistance thérapeutique

  “Electron transfer-based combination therapy of cisplatin with tetramethyl-p-phenylenediamine for ovarian, cervical, and lung cancers”

  • Luo, Ting;Yu, Jianqing;Nguyen, Jenny;Wang, Chun-Rong;Bristow, Robert G.;Jaffray, David A.;Zhou, Xiao Zhen;Lu, Kun Ping;Lu, Qing-Bin

  The platinum-based chemotherapy is the standard treatment for several types of cancer. However, cancer cells often become refractory with time and most patients with serious cancers die of drug resistance. Recently, we have discovered a unique dissociative electron-transfer mechanism of action of cisplatin, the first and most widely used platinum-based anticancer drug. Here, we show that the combination of cisplatin with an exemplary biological electron donor, N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD), may overcome the resistance of cancer cells to cisplatin. Our steady-state absorption and fluorescence spectroscopic measurements confirm the effective dissociative electron-transfer reaction between TMPD and cisplatin. More significantly, we found that the combination of 100 μM TMPD with cisplatin enhances double-strand breaks of plasmid DNA by a factor of approximately 3.5 and dramatically reduces the viability of cisplatin-sensitive human cervical (HeLa) cancer cells and ...

  
  

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

Mené sur 34 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue l'ajout du pazopanib, un agent antiangiogénique par voie orale, à un traitement combinant paclitaxel et carboplatine

• Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Mené sur 34 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue l'ajout du pazopanib, un agent antiangiogénique par voie orale, à un traitement combinant paclitaxel et carboplatine

  “Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors”

  • Burris, Howard A.;Dowlati, Afshin;Moss, Rebecca A;Infante, Jeffrey R;Jones, Suzanne F;Spigel, David R.;Levinson, Kelly T;Lindquist, Diana;Gainer, Shelby D;Dar, Mohammed M.;Suttle, A Benjamin;Ball, Howard A.;Tan, Antoinette R

  Several phase III trials have demonstrated that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the maximum tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m2 and carboplatin (dosed at area under the curve [AUC] 5 or 6) given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m2 and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with ...

  
  

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

Cet article dresse les perspectives offertes par les connaissances acquises dans le traitement d'une infection au VIH pour concevoir et évaluer des combinaisons de traitements dans le cancer

• Managing drug resistance in cancer: lessons from HIV therapy
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
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  Cet article dresse les perspectives offertes par les connaissances acquises dans le traitement d'une infection au VIH pour concevoir et évaluer des combinaisons de traitements dans le cancer

  “Managing drug resistance in cancer: lessons from HIV therapy”

  • Bock, Christoph;Lengauer, Thomas

  Drug resistance is a common cause of treatment failure for HIV infection and cancer. The high mutation rate of HIV leads to genetic heterogeneity among viral populations and provides the seed from which drug-resistant clones emerge in response to therapy. Similarly, most cancers are characterized by extensive genetic, epigenetic, transcriptional and cellular diversity, and drug-resistant cancer cells outgrow their non-resistant peers in a process of somatic evolution. Patient-specific combination of antiviral drugs has emerged as a powerful approach for treating drug-resistant HIV infection, using genotype-based predictions to identify the best matched combination therapy among several hundred possible combinations of HIV drugs. In this Opinion article, we argue that HIV therapy provides a 'blueprint' for designing and validating patient-specific combination therapies in cancer.

  
  

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

Cet article résume les données ayant servi de base à la Food and Drug Administration pour autoriser, en avril 2011, la mise sur le marché du vandetanib dans le traitement d'un cancer médullaire thyroïdien

• Vandetanib for the Treatment of Symptomatic or Progressive Medullary Thyroid Cancer in Patients with Unresectable Locally Advanced or Metastatic Disease: U.S. Food and Drug Administration Drug Approval Summary
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Cet article résume les données ayant servi de base à la Food and Drug Administration pour autoriser, en avril 2011, la mise sur le marché du vandetanib dans le traitement d'un cancer médullaire thyroïdien

  “Vandetanib for the Treatment of Symptomatic or Progressive Medullary Thyroid Cancer in Patients with Unresectable Locally Advanced or Metastatic Disease: U.S. Food and Drug Administration Drug Approval Summary”

  • Thornton, Katherine;Kim, Geoffrey;Maher, Virginia E.;Chattopadhyay, Somesh;Tang, Shenghui;Moon, Young Jin;Song, Pengfei;Marathe, Anshu;Balakrishnan, Suchitra;Zhu, Hao;Garnett, Christine;Liu, Qi;Booth, Brian;Gehrke, Brenda;Dorsam, Robert T.;Verbois, Leigh S;Ghosh, Debasis;Wilson, Wendy;Duan, John;Sarker, Haripada;Pope Miksinski, Sarah;Skarupa, Lisa;Ibrahim, Amna;Justice, Robert;Murgo, Anthony J;Pazdur, Richard

  On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa Tablets, AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced or metastatic disease. Vandetanib is the first drug approved for this indication and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib 300 mg/day orally (n=231) or to placebo (n=100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared to placebo. Other endpoints included evaluation of overall survival (OS) and objective response rate (ORR). The PFS analysis showed a marked improvement for patients randomized to vandetanib (HR=0.35; 95% CI: 0.24-0.53; p<0.0001). The objective response rate for the vandetanib arm was 44% compared ...

  
  

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

Mené sur 274 patients d'âge inférieur à 10 ans et atteints d'un gliome ne pouvant faire l'objet d'une radiothérapie, cet essai compare, du point de vue de la survie sans événement et de la survie globale, deux protocoles de chimiothérapie

• Randomized Study of Two Chemotherapy Regimens for Treatment of Low-Grade Glioma in Young Children: A Report From the Children's Oncology Group
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 274 patients d'âge inférieur à 10 ans et atteints d'un gliome ne pouvant faire l'objet d'une radiothérapie, cet essai compare, du point de vue de la survie sans événement et de la survie globale, deux protocoles de chimiothérapie

  “Randomized Study of Two Chemotherapy Regimens for Treatment of Low-Grade Glioma in Young Children: A Report From the Children's Oncology Group”

  • Ater, Joann L.;Zhou, Tianni;Holmes, Emiko;Mazewski, Claire M.;Booth, Timothy N.;Freyer, David R.;Lazarus, Ken H.;Packer, Roger J.;Prados, Michael;Sposto, Richard;Vezina, Gilbert;Wisoff, Jeffrey H.;Pollack, Ian F.

  Purpose Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury.Patients and Methods Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately.Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± ...

  
  

Mots clés : Système nerveux central; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur l'intérêt de diverses thérapies ciblées, seules ou en combinaison, pour le traitement d'un cancer du sein HER2+

• Current approaches and future directions in the treatment of HER2-positive breast cancer
  • Cancer treatment reviews, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur l'intérêt de diverses thérapies ciblées, seules ou en combinaison, pour le traitement d'un cancer du sein HER2+

  “Current approaches and future directions in the treatment of HER2-positive breast cancer”

  • Hurvitz, Sara A.;Hu, Yufang;O’Brien, Neil;Finn, Richard S.

  Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20–30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a ...

  
  

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

Mené sur 102 patientes atteintes d'un cancer métastatique du sein triplement négatif de stade IV, cet essai de phase II évalue, du point de vue du taux de réponse, l'ajout de cetuximab au carboplatine

• TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 102 patientes atteintes d'un cancer métastatique du sein triplement négatif de stade IV, cet essai de phase II évalue, du point de vue du taux de réponse, l'ajout de cetuximab au carboplatine

  “TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer”

  • Carey, Lisa A.;Rugo, Hope S.;Marcom, P. Kelly;Mayer, Erica L.;Esteva, Francisco J.;Ma, Cynthia X.;Liu, Minetta C.;Storniolo, Anna Maria;Rimawi, Mothaffar F.;Forero-Torres, Andres;Wolff, Antonio C.;Hobday, Timothy J.;Ivanova, Anastasia;Chiu, Wing-Keung;Ferraro, Madlyn;Burrows, Emily;Bernard, Philip S.;Hoadley, Katherine A.;Perou, Charles M.;Winer, Eric P.

  Purpose Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy.Patients and Methods In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m2 load then 250 mg/m2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition.Results In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of ...

  
  

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

Mené sur 457 patients atteints d'un rhabdomyosarcome embryonnaire incomplètement réséqué, cet essai compare, du point de vue de la survie globale, deux protocoles de chimiothérapie basés sur 3 et 6 molécules

• Randomized Comparison of Intensified Six-Drug Versus Standard Three-Drug Chemotherapy for High-Risk Nonmetastatic Rhabdomyosarcoma and Other Chemotherapy-Sensitive Childhood Soft Tissue Sarcomas: Long-Term Results From the International Society of Pediatr
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 457 patients atteints d'un rhabdomyosarcome embryonnaire incomplètement réséqué, cet essai compare, du point de vue de la survie globale, deux protocoles de chimiothérapie basés sur 3 et 6 molécules

  “Randomized Comparison of Intensified Six-Drug Versus Standard Three-Drug Chemotherapy for High-Risk Nonmetastatic Rhabdomyosarcoma and Other Chemotherapy-Sensitive Childhood Soft Tissue Sarcomas: Long-Term Results From the International Society of Pediatr”

  • Oberlin, Odile;Rey, Annie;Sanchez de Toledo, José;Martelli, Hélène;Jenney, Meriel E.M.;Scopinaro, Marcelo;Bergeron, Christophe;Merks, Johannes H.M.;Bouvet, Nathalie;Ellershaw, Caroline;Kelsey, Anna;Spooner, David;Stevens, Michael C.G.

  Purpose MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial.Patients and Methods From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m2 (both arms), epirubicin 450 mg/m2, etoposide 1,350 mg/m2 (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other ...

  
  
• Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  Mené sur 457 patients atteints d'un rhabdomyosarcome embryonnaire incomplètement réséqué, cet essai compare, du point de vue de la survie globale, deux protocoles de chimiothérapie basés sur 3 et 6 molécules

  “Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma”

  • Meyer, William H.

  
  

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

Mené sur 96 patients atteints d'un ostéosarcome métastatique, dont 41 présentant des tumeurs HER2+, cet essai de phase II évalue l'ajout de trastuzumab à une chimiothérapie de référence

• Phase II Trial of Trastuzumab in Combination With Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma With Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children's Oncology Group
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 96 patients atteints d'un ostéosarcome métastatique, dont 41 présentant des tumeurs HER2+, cet essai de phase II évalue l'ajout de trastuzumab à une chimiothérapie de référence

  “Phase II Trial of Trastuzumab in Combination With Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma With Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children's Oncology Group”

  • Ebb, David;Meyers, Paul;Grier, Holcombe;Bernstein, Mark;Gorlick, Richard;Lipshultz, Steven E.;Krailo, Mark;Devidas, Meenakshi;Barkauskas, Donald A.;Siegal, Gene P.;Ferguson, William Shay;Letson, George Douglas;Marcus, Karen;Goorin, Allen;Beardsley, Peter;Marina, Neyssa

  Purpose Despite efforts to intensify chemotherapy, survival for patients with metastatic osteosarcoma remains poor. Overexpression of human epidermal growth factor receptor 2 (HER2) in osteosarcoma has been shown to predict poor therapeutic response and decreased survival. This study tests the safety and feasibility of delivering biologically targeted therapy by combining trastuzumab with standard chemotherapy in patients with metastatic osteosarcoma and HER2 overexpression.Patients and Methods Among 96 evaluable patients with newly diagnosed metastatic osteosarcoma, 41 had tumors that were HER2-positive by immunohistochemistry. All patients received chemotherapy with cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide. Dexrazoxane was administered with doxorubicin to minimize the risk of cardiotoxicity from treatment with trastuzumab and anthracycline. Only patients with HER2 overexpression received concurrent therapy with trastuzumab given for 34 consecutive ...

  
  

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

Mené sur 135 patients non fumeurs atteints d'un adénocarcinome pulmonaire avancé, cet essai coréen de phase III compare, du point de vue de la survie sans progression, le gefitinib et le pemetrexed en traitement de deuxième ligne

• Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01)
  • Cancer, sous presse, 2012 (résumé)
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  Mené sur 135 patients non fumeurs atteints d'un adénocarcinome pulmonaire avancé, cet essai coréen de phase III compare, du point de vue de la survie sans progression, le gefitinib et le pemetrexed en traitement de deuxième ligne

  “Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01)”

  • Sun, Jong-Mu;Lee, Ki Hyeong;Kim, Sang-we;Lee, Dae Ho;Min, Young Joo;Yun, Hwan Jung;Kim, Hoon Kyo;Song, Hong Suk;Kim, Yeul Hong;Kim, Bong-Seog;Hwang, In Gyu;Lee, Keehyun;Jo, Sook Jung;Lee, Jae Won;Ahn, Jin Seok;Park, Keunchil;Ahn, Myung-Ju;for the Korean Cancer Study, Group

  BACKGROUND: Gefitinib was compared with pemetrexed as second-line therapy in a clinically selected population previously treated with platinum-based chemotherapy. METHODS: A phase 3 trial of gefitinib (250 mg/day) versus pemetrexed (500 mg/m2 on day 1, every 3 weeks) was conducted in patients who had never smoked and who had advanced pulmonary adenocarcinoma treated with 1 previous platinum-based regimen. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 135 patients were analyzed. The gefitinib group had significantly longer PFS compared with the pemetrexed group, with a median PFS time of 9.0 versus 3.0 months (P = .0006). The objective response rates were 58.8% and 22.4% for gefitinib and pemetrexed, respectively (P < .001). However, there was no statistically significant difference in overall survival between the 2 groups (22.2 vs 18.9 months; P = .37). The difference of PFS was increased in a subgroup analysis of 33 patients with activating epidermal ...

  
  

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

Ces deux essais évaluent l'activité et la toxicité du vismodegib, un inhibiteur de la voie Hegdehog, pour le traitement d'un naevus basocellulaire ou d'un carcinome basocellulaire avancé

• Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome
  • New England Journal of Medicine, Vol. 366 (23), pp. 2180-2188, 2012 (résumé)
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  Ces deux essais évaluent l'activité et la toxicité du vismodegib, un inhibiteur de la voie Hegdehog, pour le traitement d'un naevus basocellulaire ou d'un carcinome basocellulaire avancé

  “Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome”

  • Tang, Jean Y.;Mackay-Wiggan, Julian M.;Aszterbaum, Michelle;Yauch, Robert L.;Lindgren, Joselyn;Chang, Kris;Coppola, Carol;Chanana, Anita M.;Marji, Jackleen;Bickers, David R.;Epstein, Ervin H.

  Background: Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. Methods: We tested the anti–basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. Results: In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with ...

  
  
• Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma
  • New England Journal of Medicine, Vol. 366 (23), pp. 2171-2179, 2012 (résumé)
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  Ces deux essais évaluent l'activité et la toxicité du vismodegib, un inhibiteur de la voie Hegdehog, pour le traitement d'un naevus basocellulaire ou d'un carcinome basocellulaire avancé

  “Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma”

  • Sekulic, Aleksandar ; Migden, Michael R. ; Oro, Anthony E. ; Dirix, Luc ; Lewis, Karl D. ; Hainsworth, John D. ; Solomon, James A. ; Yoo, Simon ; Arron, Sarah T. ; Friedlander, Philip A. ; Marmur, Ellen ; Rudin, Charles M. ; Chang, Anne Lynn S. ; Low, Jennifer A. ; Mackey, Howard M. ; Yauch, Robert L. ; Graham, Richard A. ; Reddy, Josina C. ; Hauschild, Axel

  Background: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. Methods: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would ...

  
  
• Oral Hedgehog-Pathway Inhibitors for Basal-Cell Carcinoma
  • New England Journal of Medicine, Vol. 366 (23), pp. 2225-2226, 2012 (éditorial)
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  Ces deux essais évaluent l'activité et la toxicité du vismodegib, un inhibiteur de la voie Hegdehog, pour le traitement d'un naevus basocellulaire ou d'un carcinome basocellulaire localement avancé

  “Oral Hedgehog-Pathway Inhibitors for Basal-Cell Carcinoma”

  • Lear, John T.

  Basal-cell carcinoma of the skin is the most common cancer worldwide, and its prevalence is increasing, accounting for 80% of nonmelanoma skin cancers. In 2006, more than 2.1 million new cases of nonmelanoma skin cancer were treated in the United States. Basal-cell carcinoma has many clinical subtypes and can progress to an advanced state in which surgery or radiation therapy is not considered to be helpful (locally advanced basal-cell carcinoma). Such lesions arise either from earlier lesions that have not been treated or from a recurrence of aggressive basal-cell carcinoma. Metastatic basal-cell carcinoma is rare.

  
  

Mots clés : Peau (hors mélanome); Traitements (Traitements systémiques : applications cliniques)

Mené sur 115 patients atteints d'un mésothéliome malin non réséquable, cet essai de phase II évalue, du point de vue de la survie sans progression, l'ajout de bevacizumab à un traitement combinant gemcitabine et cisplatine

• Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 115 patients atteints d'un mésothéliome malin non réséquable, cet essai de phase II évalue, du point de vue de la survie sans progression, l'ajout de bevacizumab à un traitement combinant gemcitabine et cisplatine

  “Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma”

  • Kindler, Hedy L.;Karrison, Theodore G.;Gandara, David R.;Lu, Charles;Krug, Lee M.;Stevenson, James P.;Jänne, Pasi A.;Quinn, David I.;Koczywas, Marianna N.;Brahmer, Julie R.;Albain, Kathy S.;Taber, David A.;Armato, Samuel G.;Vogelzang, Nicholas J.;Chen, Helen X.;Stadler, Walter M.;Vokes, Everett E.

  Purpose Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.Patients and Methods Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo ...

  
  

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

A partir de données portant sur 5 489 patients de plus de 75 ans atteints d'un cancer colorectal de stade III opéré entre 2004 et 2007, cette étude américaine évalue le bénéfice en termes de survie associé à une chimiothérapie adjuvante dans cette population

• Effect of Adjuvant Chemotherapy on Survival of Patients With Stage III Colon Cancer Diagnosed After Age 75 Years
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  A partir de données portant sur 5 489 patients de plus de 75 ans atteints d'un cancer colorectal de stade III opéré entre 2004 et 2007, cette étude américaine évalue le bénéfice en termes de survie associé à une chimiothérapie adjuvante dans cette population

  “Effect of Adjuvant Chemotherapy on Survival of Patients With Stage III Colon Cancer Diagnosed After Age 75 Years”

  • Sanoff, Hanna K.;Carpenter, William R.;Stürmer, Til;Goldberg, Richard M.;Martin, Christopher F.;Fine, Jason P.;McCleary, Nadine Jackson;Meyerhardt, Jeffrey A.;Niland, Joyce;Kahn, Katherine L.;Schymura, Maria J.;Schrag, Deborah

  Purpose Few patients 75 years of age and older participate in clinical trials, thus whether adjuvant chemotherapy for stage III colon cancer (CC) benefits this group is unknown.Methods A total of 5,489 patients ≥ 75 years of age with resected stage III CC, diagnosed between 2004 and 2007, were selected from four data sets containing demographic, stage, treatment, and survival information. These data sets included SEER-Medicare, a linkage between the New York State Cancer Registry (NYSCR) and its Medicare programs, and prospective cohort studies Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and the National Comprehensive Cancer Network. Data sets were analyzed in parallel using covariate adjusted and propensity score (PS) matched proportional hazards models to evaluate the effect of treatment on survival. PS trimming was used to mitigate the effects of selection bias.Results Use of adjuvant therapy declined with age and comorbidity. Chemotherapy receipt was ...

  
  
• Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An Underused Lifesaving Treatment
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  A partir de données portant sur 5 489 patients de plus de 75 ans atteints d'un cancer colorectal de stade III opéré entre 2004 et 2007, cette étude américaine évalue le bénéfice en termes de survie associé à une chimiothérapie adjuvante dans cette population

  “Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An Underused Lifesaving Treatment”

  • Muss, Hyman B. ; Bynum, Debra L.

  
  

Mots clés : Colon-rectum; Traitements (Traitements systémiques : applications cliniques)

A partir d'une revue de la littérature publiée entre 2001 et 2011 (13 essais), cette méta-analyse évalue la mortalité associée à un traitement à base de sunitinib, sorafenib, pazopanib ou vandetanib chez les patients atteints d'une tumeur solide avancée

• Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: A meta-analysis
  • Cancer treatment reviews, sous presse, 2012 (résumé)
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  A partir d'une revue de la littérature publiée entre 2001 et 2011 (13 essais), cette méta-analyse évalue la mortalité associée à un traitement à base de sunitinib, sorafenib, pazopanib ou vandetanib chez les patients atteints d'une tumeur solide avancée

  “Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: A meta-analysis”

  • Sivendran, Shanthi;Liu, Ziyue;Portas, Louis J.;Yu, Menggang;Hahn, Noah;Sonpavde, Guru;Oh, William K.;Galsky, Matthew D.

  Several vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) are now approved by regulatory agencies and are important in the treatment of solid tumor malignancies. The risk of fatal adverse events (FAEs) with these agents is not well characterized. PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating sunitinib, sorafenib, pazopanib, and vandetanib in patients with all malignancies. Thirteen eligible randomized controlled trials were included in a meta-analysis and the number of FAEs (defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) criteria) was extracted and study quality was calculated. Incidence rates and relative risks were calculated for all thirteen studies as well as for the subset of patients with renal cell carcinoma. Analysis of the 5164 patients across 13 RCTs revealed that the relative risk was 1.64 (95% CI, 1.16, ...

  
  

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

Mené in vitro et sur 18 patients atteints d'un gliome primitif ou récidivant de haut grade, cet essai de phase I évalue la toxicité et la dose maximale tolérable du sorafénib combiné au témozolomide et à une radiothérapie

• A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas
  • International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)
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  Mené in vitro et sur 18 patients atteints d'un gliome primitif ou récidivant de haut grade, cet essai de phase I évalue la toxicité et la dose maximale tolérable du sorafénib combiné au témozolomide et à une radiothérapie

  “A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas”

  • Den, Robert B.;Kamrava, Mitchell;Sheng, Zhi;Werner-Wasik, Maria;Dougherty, Erin;Marinucchi, Michelle;Lawrence, Yaacov R.;Hegarty, Sarah;Hyslop, Terry;Andrews, David W.;Glass, Jon;Friedman, David P.;Green, Michael R.;Camphausen, Kevin;Dicker, Adam P.

  Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m2) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Cell viability was significantly reduced with the ...

  
  

Mots clés : Système nerveux central; Traitements (Combinaison de traitements localisés et systémiques)

Menée sur 111 patients atteints d'un cancer du poumon non à petites cellules de stade précoce et inopérable (âge : 49 à 88 ans), cette étude évalue l'intérêt d'ajouter une faible dose de gemcitabine à une radiothérapie conformationnelle tridimensionnelle pour améliorer la survie sans événement à 2 ans des patients

• Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer
  • Lung Cancer, sous presse, 2012 (résumé)
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  Menée sur 111 patients atteints d'un cancer du poumon non à petites cellules de stade précoce et inopérable (âge : 49 à 88 ans), cette étude évalue l'intérêt d'ajouter une faible dose de gemcitabine à une radiothérapie conformationnelle tridimensionnelle pour améliorer la survie sans événement à 2 ans des patients

  “Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer”

  • Price, Allan;Yellowlees, Ann;Keerie, Catriona;Russell, Susan;Faivre-Finn, Corinne;Gilligan, David;Snee, Michael;Skailes, Geraldine;Hatton, Matthew;Erridge, Sara;Mohammed, Nazia

  Background : Preclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2 year event-free survival in patients with medically inoperable stages I–II non-small cell lung cancer. Aim :To determine whether low dose gemcitabine increased event–free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery. Methods : Patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100 mg/m2 weekly gemcitabine. Results :Study entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49–88) years and 67 (63%) were male. 86 (81%) were PS 0–1 and 31 (30%) Charlson ...

  
  

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

Menée in vitro et à l'aide d'un modèle murin, cette étude évalue les effets d'un dérivé de l'arsenic (As4O6) en combinaison avec une photothérapie dynamique sur la croissance des cellules cancéreuses du col de l'utérus

• Synergistic Anti-Tumor Effects of Combination of Photodynamic Therapy and Arsenic Compound in Cervical Cancer Cells: In Vivo and In Vitro Studies
  • PLoS ONE, Vol. 7 (6), pp. e38583, 2012 (article en libre accès)
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  Menée in vitro et à l'aide d'un modèle murin, cette étude évalue les effets d'un dérivé de l'arsenic (As4O6) en combinaison avec une photothérapie dynamique sur la croissance des cellules cancéreuses du col de l'utérus

  “Synergistic Anti-Tumor Effects of Combination of Photodynamic Therapy and Arsenic Compound in Cervical Cancer Cells: In Vivo and In Vitro Studies”

  • Kim, Yong-Wan;Bae, Su Mi;Battogtokh, Gantumur;Bang, Hyo Joo;Ahn, Woong Shick

  The effects of As4O6 as adjuvant on photodynamic therapy (PDT) were studied. As4O6 is considered to have anticancer activity via several biological actions, such as free radical production and inhibition of VEGF expression. PDT or As4O6 significantly inhibited TC-1 cell proliferation in a dose-dependent manner (P<0.05) by MTT assay. The anti-proliferative effect of the combination treatment was significantly higher than in TC-1 cells treated with either photodynamic therapy or As4O6 alone (62.4 and 52.5% decrease compared to vehicle-only treated TC-1 cells, respectively, P<0.05). In addition, cell proliferation in combination of photodynamic therapy and As4O6 treatment significantly decreased by 77.4% (P<0.05). Cell survival pathway (Naip1, Tert and Aip1) and p53-dependent pathway (Bax, p21Cip1, Fas, Gadd45, IGFBP-3 and Mdm-2) were markedly increased by combination treatment of photodynamic therapy and As4O6. In addition, the immune response in the NEAT pathway (Ly-12, CD178 and IL-2) ...

  
  

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

Mené sur 23 patients atteints d'un mélanome métastatique ou d'un carcinome à cellules rénales, cet essai de phase I évalue la toxicité d'une radiothérapie stéréotaxique corporelle combinée à une forte dose d'Interleukine IL-2 et analyse la réponse immunologique associée au traitement

• Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2—Tumor and Immunological Responses
  • Science Translational Medicine, Vol. 4 (137), pp. 137ra74, 2012 (résumé)
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  Mené sur 23 patients atteints d'un mélanome métastatique ou d'un carcinome à cellules rénales, cet essai de phase I évalue la toxicité d'une radiothérapie stéréotaxique corporelle combinée à une forte dose d'Interleukine IL-2 et analyse la réponse immunologique associée au traitement

  “Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2—Tumor and Immunological Responses”

  • Seung, Steven K.;Curti, Brendan D.;Crittenden, Marka;Walker, Edwin;Coffey, Todd;Siebert, Janet C.;Miller, William;Payne, Roxanne;Glenn, Lyn;Bageac, Alexandru;Urba, Walter J.

  Preclinical models suggest that focal high-dose radiation can make tumors more immunogenic. We performed a pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) to assess safety and tumor response rate and perform exploratory immune monitoring studies. Patients with metastatic melanoma or renal cell carcinoma (RCC) who had received no previous medical therapy for metastatic disease were eligible. Patients received one, two, or three doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting IL-2. IL-2 (600,000 IU per kilogram by means of intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Patients with regressing disease received up to six IL-2 cycles. Twelve patients were included in the intent-to-treat analysis, and 11 completed treatment per the study design. Response Evaluation Criteria in Solid Tumors criteria were used to assess overall ...

  
  

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

Cette étude passe en revue la littérature récente en matière d'essais cliniques de chimiothérapies à base de taxanes pour le traitement d'un cancer du sein de stade précoce ou métastatique

• If there is no overall survival benefit in metastatic breast cancer: Does it imply lack of efficacy? Taxanes as an example
  • Cancer treatment reviews, sous presse, 2012 (résumé)
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  Cette étude passe en revue la littérature récente en matière d'essais cliniques de chimiothérapies à base de taxanes pour le traitement d'un cancer du sein de stade précoce ou métastatique

  “If there is no overall survival benefit in metastatic breast cancer: Does it imply lack of efficacy? Taxanes as an example”

  • Vriens, Birgit E. P. J.;Lobbezoo, Dorien J. A.;de Hoon, Joep P. J.;Veeck, Jürgen;Voogd, Adri C.;Tjan-Heijnen, Vivianne C. G.

  In recent years, new drugs have shown activity in metastatic breast cancer, but not always resulting in an overall survival benefit. This has led to discussions if such drugs, mainly expensive drugs, should be reimbursed especially when also not leading to improvement in quality of life. For that reason, we decided to systematically review taxane-based chemotherapy studies in early and metastatic breast cancer, to assess which factors may have caused the differential outcome. Taxanes did not improve survival in metastatic breast cancer trials, whereas they did so in early breast cancer trials. We questioned if the differential outcome of taxanes in metastatic breast cancer might be caused by the chosen comparator and study design. We noticed that in the majority of metastatic breast cancer studies taxanes were used as a substitute for other active cytotoxic drugs, mainly cyclophosphamide, whereas in early breast cancer studies taxanes were generally delivered in addition to a standard ...

  
  

Mots clés : Sein; Traitements (Ressources et infrastructures (Traitements))

Cet article passe en revue les perspectives offertes par les nanotechnologies pour le diagnostic et le traitement des cancers

• Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Cet article passe en revue les perspectives offertes par les nanotechnologies pour le diagnostic et le traitement des cancers

  “Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance”

  • Zamboni, William C.;Torchilin, Vladimir;Patri, Anil K.;Hrkach, Jeff;Stern, Stephen;Lee, Robert;Nel, Andre;Panaro, Nicholas J.;Grodzinski, Piotr

  Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues, which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities that are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems that could not ...

  
  

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

A partir de données portant sur 34 734 participants à un essai clinique enregistré dans la base de données "EORTC Safety", cette étude évalue les conséquences de l'absence d'une autopsie pour identifier un décès toxique

• A systemic review of Toxic Death in clinical oncology trials: an Achilles/' heel in safety reporting revisited
  • British Journal of Cancer, sous presse, 2012 (résumé)
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  A partir de données portant sur 34 734 participants à un essai clinique enregistré dans la base de données "EORTC Safety", cette étude évalue les conséquences de l'absence d'une autopsie pour identifier un décès toxique

  “A systemic review of Toxic Death in clinical oncology trials: an Achilles/' heel in safety reporting revisited”

  • Penninckx, B.;Van de Voorde, W. M.;Casado, A.;Reed, N.;Moulin, C.;Karrasch, M.

  Background: Toxic death is defined as study treatment-related mortality and as such is considered as an iatrogenic death. This belongs to unnatural death where an autopsy is advised. Until now, conventional autopsy is the gold standard to discriminate between pre- and post-mortem discrepancies. Methods: The consequences of lack of systematically performing an autopsy will be explored in the setting of oncological clinical trials. Results: During more than one decade, 6428 Serious Adverse Events have been registered in the EORTC Safety database on a total of 34 734 subjects. The number of deaths were 764 (mortality rate of 2.2%) whereof 255 (rate of 0.7%) toxic deaths. In 89.8% of these toxic deaths, no autopsy has been done; in 25.1% (64 cases) an inconsistent cause of death was found based on studying of the medical narrative. The autopsy rate was only 10.2% (26 out of 255) and, in 46.2% of the performed autopsies, there was a clinical pathological discrepancy. Conclusion: When no ...

  
  

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

Cette étude évalue la capacité d'une méthode de simulation numérique à prédire les cibles biologiques d'une molécule en développement et, ainsi, à identifier aussi tôt que possible ses effets indésirables potentiels

• Large-scale prediction and testing of drug activity on side-effect targets
  • Nature, sous presse, 2012 (résumé)
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  Cette étude évalue la capacité d'une méthode de simulation numérique à prédire les cibles biologiques d'une molécule en développement et, ainsi, à identifier aussi tôt que possible ses effets indésirables potentiels

  “Large-scale prediction and testing of drug activity on side-effect targets”

  • Lounkine, Eugen;Keiser, Michael J.;Whitebread, Steven;Mikhailov, Dmitri;Hamon, Jacques;Jenkins, Jeremy L.;Lavan, Paul;Weber, Eckhard;Doak, Allison K.;Cote, Serge;Shoichet, Brian K.;Urban, Laszlo

  Discovering the unintended ‘off-targets’ that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended ‘side-effect’ targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 μM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug –target–adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated ...

  
  
• Drug discovery: Computer model predicts side effects
  • Nature, sous presse, 2012 (commentaire)
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  Cette étude évalue la capacité d'une méthode de simulation numérique à prédire les cibles biologiques d'une molécule en développement et, ainsi, à identifier aussi tôt que possible ses effets indésirables potentiels

  “Drug discovery: Computer model predicts side effects”

  • Kolaja, Kyle

  Drug candidates are usually found to be unsafe only late in the drug discovery process. A method for predicting the many biological targets of a given molecule might allow drug safety to be considered much earlier.

  
  

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

A partir de travaux menés sur la drosophile, cette étude évalue la faisabilité d'une méthode dite de pharmacologie des systèmes pour identifier des composés inhibiteurs de kinase dotés d'une efficacité thérapeutique maximale

• Chemical genetic discovery of targets and anti-targets for cancer polypharmacology
  • Nature, Vol. 486 (7401), pp. 80-84, 2012 (résumé)
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  A partir de travaux menés sur la drosophile, cette étude évalue la faisabilité d'une méthode dite de pharmacologie des systèmes pour identifier des composés inhibiteurs de kinase dotés d'une efficacité thérapeutique maximale

  “Chemical genetic discovery of targets and anti-targets for cancer polypharmacology”

  • Dar, Arvin C.;Das, Tirtha K.;Shokat, Kevan M.;Cagan, Ross L.

  The complexity of cancer has led to recent interest in polypharmacological approaches for developing kinase-inhibitor drugs; however, optimal kinase-inhibition profiles remain difficult to predict. Using a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling, here we identify that AD57 rescues oncogenic Ret-induced lethality, whereas related Ret inhibitors imparted reduced efficacy and enhanced toxicity. Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity. Inhibition of Ret plus Raf, Src and S6K was required for optimal animal survival, whereas inhibition of the ‘anti-target’ Tor led to toxicity owing to release of negative feedback. Rational synthetic tailoring to eliminate Tor binding afforded AD80 and AD81, compounds featuring balanced pathway inhibition, improved efficacy and low toxicity in Drosophila and mammalian multiple endocrine ...

  
  

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