Accueil Nota Bene Cancer V2 Numéro 136 du 15 Mai 2012 Traitements

Nota Bene Cancer Numéro 136 du 15 Mai 2012

Traitements

Traitements localisés : découverte et développement

Menée sur 52 patients atteints d'un cancer de la tête et du cou, cette étude évalue la faisabilité d'une radiothérapie guidée par l'image et basée sur la tomothérapie hélicoïdale pour réduire la dose de rayonnements affectant la glande parotide controlatérale

Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer
• BMC Cancer, Vol. 12 (1), pp. 175, 2012 (article en libre accès)

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Menée sur 52 patients atteints d'un cancer de la tête et du cou, cette étude évalue la faisabilité d'une radiothérapie guidée par l'image et basée sur la tomothérapie hélicoïdale pour réduire la dose de rayonnements affectant la glande parotide controlatérale

“Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer”

• Nguyen, Nam;Vos, Paul;Vinh-Hung, Vincent;Ceizyk, Misty;Smith-Raymond, Lexie;Stevie, Michelle;Slane, Benjamin;Chi, Alexander;Desai, Anand;Krafft, Shane;Jang, Siyoung;Hamilton, Russ;Karlsson, Ulf;Abraham, Dave

BACKGROUND:To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastasesMETHODS:A retrospective review of 52 patients undergoing radiation for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed.RESULTS:Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was,respectively,14.1 Gy and 24.& Gy for the SC and CC plans (p<0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% ...

Mots clés : Voies aérodigestives supérieures; Traitements (Traitements localisés : découverte et développement)

Menée sur 85 patients atteints d'un rétinoblastome entre 1998 et 2008 (âge médian : 28 ans ; durée médiane de suivi : 72,8 mois), cette étude rétrospective évalue, du point de vue du contrôle local à 2 ans de la maladie, l'efficacité d'un traitement épiscléral préservant l'oeil et utilisant une plaque radioactive à base de ruthénium 106

106Ruthenium Plaque Therapy (RPT) for Retinoblastoma
• International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)

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Menée sur 85 patients atteints d'un rétinoblastome entre 1998 et 2008 (âge médian : 28 ans ; durée médiane de suivi : 72,8 mois), cette étude rétrospective évalue, du point de vue du contrôle local à 2 ans de la maladie, l'efficacité d'un traitement épiscléral préservant l'oeil et utilisant une plaque radioactive à base de ruthénium 106

“106Ruthenium Plaque Therapy (RPT) for Retinoblastoma”

• Murakami, Naoya;Suzuki, Shigenobu;Ito, Yoshinori;Yoshimura, Ryoichi;Inaba, Koji;Kuroda, Yuki;Morota, Madoka;Mayahara, Hiroshi;Sakudo, Mototake;Wakita, Akihisa;Okamoto, Hiroyuki;Sumi, Minako;Kagami, Yoshikazu;Nakagawa, Keiichi;Ohtomo, Kuni;Itami, Jun

To evaluate the effectiveness of episcleral 106ruthenium plaque therapy (RPT) in the management of retinoblastoma. One hundred one RPTs were retrospectively analyzed that were performed in 90 eyes of 85 patients with retinoblastoma at National Cancer Center Hospital between 1998 and 2008. Each RPT had a corresponding tumor and 101 tumors were considered in the analysis of local control. Median follow-up length was 72.8 months. Median patient age at the RPT was 28 months. Median prescribed doses at reference depth and outer surface of the sclera were 47.4 Gy and 162.3 Gy, respectively. Local control rate (LCR) and ocular retention rate (ORR) at 2 years were 33.7% and 58.7%, respectively. Unilateral disease, International Classification of Retinoblastoma group C or more advanced at the first presentation or at the time of RPT, vitreous and/or subretinal seeding, tumor size greater than 5 disc diameter (DD), reference depth greater than 5 mm, dose rate at reference depth lower than 0.7 ...

Mots clés : Autres organes; Traitements (Traitements localisés : découverte et développement)

Traitements localisés : applications cliniques

Cet article passe en revue les points essentiels concernant la préparation des patients, l'équipe chirurgicale, la technique et les outils utilisés lors d'une néphrectomie partielle assistée par robot puis fait le point sur les soins post-opératoires et les résultats cliniques associés à l'opération

Current status of robot-assisted partial nephrectomy
• BJU International, sous presse, 2012 (résumé)

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Cet article passe en revue les points essentiels concernant la préparation des patients, l'équipe chirurgicale, la technique et les outils utilisés lors d'une néphrectomie partielle assistée par robot puis fait le point sur les soins post-opératoires et les résultats cliniques associés à l'opération

“Current status of robot-assisted partial nephrectomy”

• Gohil, Rishma;Ahmed, Kamran;Kooiman, Gordon;Khan, Mohammed Shamim;Dasgupta, Prokar;Challacombe, Ben

What's known on the subject? and What does the study add? The use of robotic assistance for the partial nephrectomy procedure has emerged as an alternative that may help some of the technical challenges of laparoscopic partial nephrectomy. The main concerns in laparoscopic partial nephrectomy relates to a steeper ‘learning curve’, prolonged warm ischaemia times and the potential for postoperative haemorrhage. The article delineates the dynamics of patient preparation, the surgical team, surgical technique & post-operative care to conclude that robotic-assisted partial nephrectomy is a viable alternative to both open and laparoscopic techniques. Partial nephrectomy has shown both improved overall patient survival and more effective preservation of renal function, when compared with radical nephrectomy. Robot-assisted partial nephrectomy has several potential advantages over the laparoscopic approach. Robotic assistance allows urologists to perform this complex reconstructive ...

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

Mené au Japon sur 351 patients atteints d'un cancer du bas rectum de stade II ou III, cet essai randomisé multicentrique évalue la morbidité et la mortalité hospitalière après une excision mésorectale avec ou sans curage ganglionnaire latéral

Postoperative morbidity and mortality after mesorectal excision with and without lateral lymph node dissection for clinical stage II or stage III lower rectal cancer (JCOG0212): results from a multicentre, randomised controlled, non-inferiority trial
• The Lancet Oncology, sous presse, 2012 (résumé)

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Mené au Japon sur 351 patients atteints d'un cancer du bas rectum de stade II ou III, cet essai randomisé multicentrique évalue la morbidité et la mortalité hospitalière après une excision mésorectale avec ou sans curage ganglionnaire latéral

“Postoperative morbidity and mortality after mesorectal excision with and without lateral lymph node dissection for clinical stage II or stage III lower rectal cancer (JCOG0212): results from a multicentre, randomised controlled, non-inferiority trial”

• Fujita, Shin;Akasu, Takayuki;Mizusawa, Junki;Saito, Norio;Kinugasa, Yusuke;Kanemitsu, Yukihide;Ohue, Masayuki;Fujii, Shoichi;Shiozawa, Manabu;Yamaguchi, Takashi;Moriya, Yoshihiro

Mesorectal excision is the international standard surgical procedure for lower rectal cancer. However, lateral pelvic lymph node metastasis occasionally occurs in patients with clinical stage II or stage III rectal cancer, and therefore mesorectal excision with lateral lymph node dissection is the standard procedure in Japan. We did a randomised controlled trial to confirm that the results of mesorectal excision alone are not inferior to those of mesorectal excision with lateral lymph node dissection. This study was undertaken at 33 major hospitals in Japan. Eligibility criteria included histologically proven rectal cancer of clinical stage II or stage III, with the main lesion located in the rectum with the lower margin below the peritoneal reflection, and no lateral pelvic lymph node enlargement. After surgeons had confirmed macroscopic R0 resection by mesorectal excision, patients were intraoperatively randomised to mesorectal excision alone or with lateral lymph node dissection. ...
Exploring the limits in low rectal cancer
• The Lancet Oncology, sous presse, 2012 (commentaire)

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Mené au Japon sur 351 patients atteints d'un cancer du bas rectum de stade II ou III, cet essai randomisé multicentrique évalue la morbidité et la mortalité hospitalière après une excision mésorectale avec ou sans curage ganglionnaire latéral

“Exploring the limits in low rectal cancer”

• Moran, Brendan

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

Cet article passe en revue les études récentes concernant les avantages, les inconvénients et le coût de la chirurgie assistée par robot pour traiter un cancer du col de l'utérus, de l'endomètre ou de l'ovaire

Robotic surgery in gynecologic oncology
• Current Opinion in Oncology, sous presse, 2012 (résumé)

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Cet article passe en revue les études récentes concernant les avantages, les inconvénients et le coût de la chirurgie assistée par robot pour traiter un cancer du col de l'utérus, de l'endomètre ou de l'ovaire

“Robotic surgery in gynecologic oncology”

• Fleming, Nicole D.;Ramirez, Pedro T.

Purpose of review: The objective of this article is to review the recently published literature on the use of robotic surgery in the management of gynecologic malignancies. Recent findings: Retrospective data collected from many institutions support the use of robotic surgery in the management of cervical, endometrial, and early-stage ovarian cancer. Benefits to robotic surgery include decreased blood loss, fewer perioperative complications, and decreased length of hospital stay, especially when compared to an open cohort. Disadvantages include costs associated with the robotic system and disposable equipment, accessibility to robotic surgical systems, loss of haptic sensation with the device, and lack of prospective trials validating its use in gynecologic oncology. Summary: Current evidence establishes a role for the use of robotic surgery in the treatment of gynecologic malignancies. Further research should be implemented to validate the use of robotic surgery in gynecologic ...

Mots clés : Col de l'utérus; Traitements (Traitements localisés : applications cliniques)

Traitements systémiques : découverte et développement

Menée in vitro et in vivo, cette étude évalue l'efficacité du dasatinib, un inhibiteur de kinases de la famille Src, dans la réduction de la croissance tumorale et la prévention des métastases des cancers de la thyroïde

Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis
• Clinical Cancer Research, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude évalue l'efficacité du dasatinib, un inhibiteur de kinases de la famille Src, dans la réduction de la croissance tumorale et la prévention des métastases des cancers de la thyroïde

“Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis”

• Chan, Christine M.;Jing, Xia;Pike, Laura A.;Zhou, Qiong;Lim, Dong-Jun;Sams, Sharon B.;Lund, Gregory S.;Sharma, Vibha;Haugen, Bryan R.;Schweppe, Rebecca E.

Purpose: There are no effective therapies for patients with poorly differentiated thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src Family Kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis. Experimental Design: The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis was evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using a Src-gatekeeper mutant. ...

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

Menée in vitro et in vivo, cette étude suggère que des inhibiteurs de MEK pourraient être efficaces dans les glioblastomes présentant un déficit en neurofibromine 1

Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency
• Cancer Research, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude suggère que des inhibiteurs de MEK pourraient être efficaces dans les glioblastomes présentant un déficit en neurofibromine 1

“Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency”

• See, Wendy L;Tan, I-Li;Mukherjee, Joydeep;Nicolaides, Theodore;Pieper, Russell O

Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and PI3-kinase/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor-sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor-sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did notactivate the PI3-kinase ...

Mots clés : Système nerveux central; Traitements (Traitements systémiques : découverte et développement)

Menée sur des lignées cellulaires de cancer du sein et à l'aide de xénogreffes, cette étude évalue la capacité d'un composé appelé GDC-0941, un inhibiteur sélectif de PI3K par voie orale, à augmenter l'activité antitumorale du docétaxel

GDC-0941, A Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo
• Clinical Cancer Research, sous presse, 2012 (résumé)

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Menée sur des lignées cellulaires de cancer du sein et à l'aide de xénogreffes, cette étude évalue la capacité d'un composé appelé GDC-0941, un inhibiteur sélectif de PI3K par voie orale, à augmenter l'activité antitumorale du docétaxel

“GDC-0941, A Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo”

• Wallin, Jeffrey J.;Guan, Jane;Prior, Wei Wei;Lee, Leslie;Berry, Leanne;Belmont, Lisa D.;Koeppen, Hartmut;Belvin, Marcia;Friedman, Lori S.;Sampath, Deepak

Purpose: Docetaxel (DTX) is a front-line standard of care chemotherapeutic drug for the treatment of breast cancer. Phosphatidylinositol 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration and survival. The current study was intended to determine if GDC-0941, an orally bioavailable class I selective PI3K inhibitor, enhances the anti-tumor activity of DTX in human breast cancer models in vitro and in vivo. Experimental Design: A panel of 25 breast tumor cell lines representing HER2+, luminal and basal subtypes were treated with GDC-0941, DTX or the combination of both drugs and assayed for cellular viability, modulation of PI3K pathway markers and apoptosis induction. Drug combination effects on cellular viability were also assessed in non-transformed MCF10A human mammary epithelial cells. Human xenografts of breast cancer cell lines and patient-derived tumors were utilized to assess efficacy of GDC-0941 and DTX in vivo. Results: Combination of GDC-0941 ...

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

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude montre notamment qu'un inhibiteur d'EGFR sensibilise des cellules de cancer du sein triplement négatif à un agent cytotoxique si les deux molécules sont administrées en séquence et non simultanément

Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks
• Cell, Vol. 149 (4), pp. 780-794, 2012 (résumé)

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Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude montre notamment qu'un inhibiteur d'EGFR sensibilise des cellules de cancer du sein triplement négatif à un agent cytotoxique si les deux molécules sont administrées en séquence et non simultanément

“Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks”

• Lee, Michael J;Ye, Albert S;Gardino, Alexandra K;Heijink, Anne Margriet;Sorger, Peter K;MacBeath, Gavin;Yaffe, Michael B

Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to ...
Network Medicine Strikes a Blow against Breast Cancer
• Cell, Vol. 149 (4), pp. 731-733, 2012 (commentaire)

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Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude montre notamment qu'un inhibiteur d'EGFR sensibilise des cellules de cancer du sein triplement négatif à un agent cytotoxique si les deux molécules sont administrées en séquence et non simultanément

“Network Medicine Strikes a Blow against Breast Cancer”

• Erler, Janine T. ; Linding, Rune

Drug development for complex diseases is shifting from targeting individual proteins or genes to systems-based attacks targeting dynamic network states. Lee et al. now reveal how the progressive rewiring of a signaling network over time following EGF receptor inhibition leaves triple-negative breast tumors vulnerable to a second, later hit with DNA-damaging drugs, demonstrating that time- and order-dependent drug combinations can be more efficacious in killing cancer cells.

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

Menée à partir de lignées cellulaires et d'échantillons tumoraux, cette étude identifie, parmi plus de 1 200 molécules autorisées, le niclosamide (un anthelminthique) comme étant doté d'une activité intéressante contre les cellules souches de cancer ovarien

Growth inhibition of ovarian tumor-initiating cells by niclosamide
• Molecular Cancer Therapeutics, sous presse, 2012 (résumé)

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Menée à partir de lignées cellulaires et d'échantillons tumoraux, cette étude identifie, parmi plus de 1 200 molécules autorisées, le niclosamide (un anthelminthique) comme étant doté d'une activité intéressante contre les cellules souches de cancer ovarien

“Growth inhibition of ovarian tumor-initiating cells by niclosamide”

• Yo, Yi-Te;Lin, Ya-Wen;Wang, Yu-Chi;Balch, Curt;Huang, Rui-Lan;Chan, Michael W. Y.;Sytwu, Huey-Kang;Chen, Chi-Kuan;Chang, Cheng-Chang;Nephew, Kenneth P.;Huang, Tim H. M.;Yu, Mu-Hsien;Lai, Hung-Cheng

A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that targets such primitive cells. To discover such novel compounds active against drug resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells, from cell lines and patient tumors, using .multiple "stemness" phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTICs) to high throughput drug screening, using > 1200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments demonstrated that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays ...

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

Mené sur 75 patients atteints d'une leucémie myéloïde aiguë ou d'un syndrome myélodysplasique, cet essai de phase II évalue la toxicité et l'activité d'un traitement combinant le vorinostat, un inhibiteur d'histone déacétylase, avec l'idarubicine et la cytarabine

Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 75 patients atteints d'une leucémie myéloïde aiguë ou d'un syndrome myélodysplasique, cet essai de phase II évalue la toxicité et l'activité d'un traitement combinant le vorinostat, un inhibiteur d'histone déacétylase, avec l'idarubicine et la cytarabine

“Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome”

• Garcia-Manero, Guillermo;Tambaro, Francesco Paolo;Bekele, Nebiyou B.;Yang, Hui;Ravandi, Farhad;Jabbour, Elias;Borthakur, Gautam;Kadia, Tapan M.;Konopleva, Marina Y.;Faderl, Stefan;Cortes, Jorge E.;Brandt, Mark;Hu, Yumin;McCue, Deborah;Newsome, Willie Mae;Pierce, Sherry R.;de Lima, Marcos;Kantarjian, Hagop M.

Purpose To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).Patients And Methods Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely.Results After a three-patient run-in ...

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

Menée sur des lignées cellulaires de cancers du sein et du côlon, ainsi qu'à l'aide de xénogreffes, cette étude évalue la capacité d'un composé appelé KU-0060648, un inhibiteur dual de DNA-PK et PI-3K, à augmenter la cytoxicité de l'étoposide et de la doxorubiciine

Chemosensitisation of cancer cells by KU-0060648; a dual inhibitor of DNA-PK and PI-3K
• Molecular Cancer Therapeutics, sous presse, 2012 (résumé)

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Menée sur des lignées cellulaires de cancers du sein et du côlon, ainsi qu'à l'aide de xénogreffes, cette étude évalue la capacité d'un composé appelé KU-0060648, un inhibiteur dual de DNA-PK et PI-3K, à augmenter la cytoxicité de l'étoposide et de la doxorubiciine

“Chemosensitisation of cancer cells by KU-0060648; a dual inhibitor of DNA-PK and PI-3K”

• Munck, Joanne M;Batey, Michael A;Zhao, Yan;Jenkins, Helen;Richardson, Caroline J;Cano, Celine;Tavecchio, Michele;Barbeau, Jody;Bardos, Julia;Cornell, Liam;Griffin, Roger J;Menear, Keith A;Slade, Andrew;Thommes, Pia;Martin, Niall MB;Newell, David R;Smith, Graeme C.M.;Curtin, Nicola J

DNA double strand breaks (DSBs) are the most cytotoxic lesions induced by topoisomerase II poisons. Non-homologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-PK activity. DNA-PKcs is structurally similar to PI-3K, which promotes cell survival and proliferation and is up-regulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK auto-phosphorylation with IC50 values of 0.019 µM (MCF7 cells) and 0.17 µM (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC50 values of 0.039 µM (MCF7 cells) and > 10 µM (SW620 cells). 5-day exposure to 1 µM KU-0060648 inhibited cell proliferation by > 95% in MCF7 cells, but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in ...

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

Cet article passe en revue les perspectives offertes par les travaux récents sur les mécanismes non apoptotiques de mort cellulaire pour développer des traitements du cancer

Killing a cancer: what are the alternatives?
• Nature Reviews Cancer, sous presse, 2012 (résumé)

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Cet article passe en revue les perspectives offertes par les travaux récents sur les mécanismes non apoptotiques de mort cellulaire pour développer des traitements du cancer

“Killing a cancer: what are the alternatives?”

• Kreuzaler, Peter;Watson, Christine J.

Evading programmed cell death is one of the hallmarks of cancer. Conversely, inducing cell death by pharmacological means is the basis of almost every non-invasive cancer therapy. Research over the past decade has greatly increased our understanding of non-apoptotic programmed cell death events, such as lysosomal-mediated cell death, necroptosis and cell death with autophagy. It is becoming clear that an intricate effector network connects many of these classical and non-classical death pathways. In this Review, we discuss converging and diverging features of these pathways, as well as attempts to exploit this newly gained knowledge pharmacologically to provide therapeutics for cancer.

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

Menée in vitro et in vivo, cette étude met en évidence des mécanismes d'action antitumorale et antimétastatique d'un composé appelé SAR131675, un inhibiteur sélectif de l'activité tyrosine kinase de VEGFR-3

SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic,anti-tumoral and anti-metastatic activities
• Molecular Cancer Therapeutics, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude met en évidence des mécanismes d'action antitumorale et antimétastatique d'un composé appelé SAR131675, un inhibiteur sélectif de l'activité tyrosine kinase de VEGFR-3

“SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic,anti-tumoral and anti-metastatic activities”

• Alam, Antoine;Blanc, Isabelle;Gueguen-Dorbes, Geneviève;Duclos, Olivier;Bonnin, Jacques;Barron, Pauline;Laplace, Marie-Claude;Morin, Gaelle;Gaujarengues, Florence;Dol, Frederique;Hérault, Jean-Pascal;Schaeffer, Paul;Savi, Pierre;Bono, Françoise

SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase (TK) activity and VEGFR-3 autophosphorylation in HEK cells with IC50s of 20nM and 45nM, respectively. SAR131675 dose-dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC50 of about 20nM. SAR131675 was found to be highly selective for VEGFR-3 versus 107 receptors, enzymes, ion channels and 65 kinases. However, it exhibited a moderate activity on VEGFR-2 with a VEGFR-3/VEGFR-2 ratio of about 10. SAR131675 had no anti-proliferative activity on a panel of 30 tumors and primary cells, further demonstrating its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. SAR131675 was very well tolerated in mice and demonstrated a potent antitumoral effect in several orthotopic and syngenic models including mammary 4T1 carcinoma and the RIP1.Tag2 tumors. Interestingly, it significantly reduced ...

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

Traitements systémiques : applications cliniques

Mené sur 553 patients atteints d'un cancer superficiel de la vessie sans carcinome in situ, cet essai de phase III compare, du point de vue de la survie sans récidive, une immunothérapie à base d'hémocyanine de patelle avec la mitomycine

Intracutaneous and Intravesical Immunotherapy With Keyhole Limpet Hemocyanin Compared With Intravesical Mitomycin in Patients With Non–Muscle-Invasive Bladder Cancer: Results From a Prospective Randomized Phase III Trial
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 553 patients atteints d'un cancer superficiel de la vessie sans carcinome in situ, cet essai de phase III compare, du point de vue de la survie sans récidive, une immunothérapie à base d'hémocyanine de patelle avec la mitomycine

“Intracutaneous and Intravesical Immunotherapy With Keyhole Limpet Hemocyanin Compared With Intravesical Mitomycin in Patients With Non–Muscle-Invasive Bladder Cancer: Results From a Prospective Randomized Phase III Trial”

• Lammers, Rianne J.M.;Witjes, Wim P.J.;Janzing-Pastors, Maria H.D.;Caris, Christien T.M.;Witjes, J. Alfred

Purpose Despite current treatment after transurethral resection of a bladder tumor, recurrences and progression remain a problem. Keyhole limpet hemocyanin (KLH) was beneficial in earlier studies. In this study, safety and efficacy of KLH were compared with that of mitomycin (MM).Patients and Methods Patients with intermediate- and high-risk non–muscle-invasive bladder cancer (NMIBC) without carcinoma in situ were enrolled in a randomized phase III trial. In all, 283 patients were randomly assigned for 16 adjuvant intravesical instillations with KLH after preimmunization, and 270 patients were randomly assigned for 11 adjuvant intravesical instillations with MM. Primary outcome measurement was recurrence-free survival (RFS). Secondary outcome measurements were progression-free survival, adverse events (AEs), and the effect of delayed-type hypersensitivity (DTH) response on clinical outcome.Results There were significantly more pT1 tumors in the MM group (P = .01). In a log-rank ...

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

Mené sur 269 patients atteints d'un myélome multiple progressant ou récidivant après une greffe autologue de cellules souches, cet essai de phase III évalue, du point de vue de la durée médiane avant progression, l'ajout de bortezomib à un traitement combinant thalidomide et dexaméthasone

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomi
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 269 patients atteints d'un myélome multiple progressant ou récidivant après une greffe autologue de cellules souches, cet essai de phase III évalue, du point de vue de la durée médiane avant progression, l'ajout de bortezomib à un traitement combinant thalidomide et dexaméthasone

“Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomi”

• Garderet, Laurent;Iacobelli, Simona;Moreau, Philippe;Dib, Mamoun;Lafon, Ingrid;Niederwieser, Dietger;Masszi, Tamas;Fontan, Jean;Michallet, Mauricette;Gratwohl, Alois;Milone, Giuseppe;Doyen, Chantal;Pegourie, Brigitte;Hajek, Roman;Casassus, Philippe;Kolb, Brigitte;Chaleteix, Carine;Hertenstein, Bernd;Onida, Francesco;Ludwig, Heinz;Ketterer, Nicolas;Koenecke, Christian;van Os, Marleen;Mohty, Mohamad;Cakana, Andrew;Gorin, Norbert Claude;de Witte, Theo;Harousseau, Jean Luc;Morris, Curly;Gahrton, Gösta

Purpose This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT).Patients and Methods Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m2 intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months).Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P ...
The Era of Combination Therapy in Myeloma
• Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)

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Mené sur 269 patients atteints d'un myélome multiple progressant ou récidivant après une greffe autologue de cellules souches, cet essai de phase III évalue, du point de vue de la durée médiane avant progression, l'ajout de bortezomib à un traitement combinant thalidomide et dexaméthasone

“The Era of Combination Therapy in Myeloma”

• Lonial, Sagar ; Kaufman, Jonathan L.

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

Mené sur 320 patients atteints d'une leucémie myéloïde aiguë récidivante ou réfractaire (âge médian : 67 ans), cet essai évalue, du point de vue de la survie globale, l'ajout de clofarabine à la cytarabine

Clofarabine Plus Cytarabine Compared With Cytarabine Alone in Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia: Results From the CLASSIC I Trial
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 320 patients atteints d'une leucémie myéloïde aiguë récidivante ou réfractaire (âge médian : 67 ans), cet essai évalue, du point de vue de la survie globale, l'ajout de clofarabine à la cytarabine

“Clofarabine Plus Cytarabine Compared With Cytarabine Alone in Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia: Results From the CLASSIC I Trial”

• Faderl, Stefan;Wetzler, Meir;Rizzieri, David;Schiller, Gary;Jagasia, Madan;Stuart, Robert;Ganguly, Siddhartha;Avigan, David;Craig, Michael;Collins, Robert;Maris, Michael;Kovacsovics, Tibor;Goldberg, Stuart;Seiter, Karen;Hari, Parameswaran;Greiner, Jochen;Vey, Norbert;Recher, Christian;Ravandi, Farhad;Wang, Eunice S.;Vasconcelles, Michael;Huebner, Dirk;Kantarjian, Hagop M.

Purpose To compare the receipt of clofarabine plus cytarabine (Clo+Ara-C arm) with cytarabine (Ara-C arm) in patients ≥ 55 years old with refractory or relapsed acute myelogenous leukemia (AML).Patients and Methods Patients were randomly assigned to receive either clofarabine (Clo) 40 mg/m2 or a placebo followed by Ara-C 1 g/m2 for five consecutive days. The primary end point was overall survival (OS). Secondary end points included event-free survival (EFS), 4-month EFS, overall remission rate (ORR; complete remission [CR] plus CR with incomplete peripheral blood count recovery), disease-free survival (DFS), duration of remission (DOR), and safety.Results Among 320 patients with confirmed AML (median age, 67 years), the median OS was 6.6 months in the Clo+Ara-C arm and 6.3 months in the Ara-C arm (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00). The ORR was 46.9% in the Clo+Ara-C arm (35.2% CR) versus 22.9% in the Ara-C arm (17.8% CR; P < .01). EFS (HR: 0.63; 95% CI, 0.49 ...

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

Cet article passe en revue les travaux récents sur l'immunothérapie des cancers

Immunotherapy of cancer in 2012
• CA: A Cancer Journal for Clinicians, sous presse, 2012 (article en libre accès)

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Cet article passe en revue les travaux récents sur l'immunothérapie des cancers

“Immunotherapy of cancer in 2012”

• Kirkwood, John M.;Butterfield, Lisa H.;Tarhini, Ahmad A.;Zarour, Hassane;Kalinski, Pawel;Ferrone, Soldano

The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an ...

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

Combinaison de traitements localisés et systémiques

Menée in vitro et à l'aide d'une xénogreffe orthotopique de carcinome anaplasique de la thyroïde, cette étude montre que l'inhibition de la glycolyse des cellules tumorales modifie leur métabolisme et améliore leur réponse à la chimiothérapie et à la radiothérapie

Glycolytic Inhibition Alters Anaplastic Thyroid Carcinoma Tumor Metabolism and Improves Response to Conventional Chemotherapy and Radiation
• Molecular Cancer Therapeutics, sous presse, 2012 (résumé)

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Menée in vitro et à l'aide d'une xénogreffe orthotopique de carcinome anaplasique de la thyroïde, cette étude montre que l'inhibition de la glycolyse des cellules tumorales modifie leur métabolisme et améliore leur réponse à la chimiothérapie et à la radiothérapie

“Glycolytic Inhibition Alters Anaplastic Thyroid Carcinoma Tumor Metabolism and Improves Response to Conventional Chemotherapy and Radiation”

• Sandulache, Vlad C.;Skinner, Heath D.;Wang, Yuan;Chen, Yunyun;Dodge, Cristina T.;Ow, Thomas J.;Bankson, James A.;Myers, Jeffrey N.;Lai, Stephen Y.

Anaplastic thyroid carcinoma (ATC) accounts for more than 50% of thyroid cancer mortality and is generally refractory to conventional treatment. On the basis of recent studies, we hypothesized that ATC metabolism can be targeted to improve response to chemoradiotherapy. Eight established and authenticated ATC cell lines were sequenced at 140 sites contained within 26 commonly mutated genes to identify novel potential therapeutic targets. Cellular proliferation, energy, and reducing potential stores were measured under conditions of specific nutrient deprivation. Tumor metabolism was evaluated using hyperpolarized 13C MRI in a murine orthotopic xenograft model of ATC. Sensitivity to chemotherapeutic agents and radiation (XRT) was assayed using cytotoxicity assays. We identified mutations in BRAF, NRAS, and KIT but failed to identify generalized novel targets for therapeutic intervention. ATC cell lines exhibited a mesenchymal phenotype and generalized dependence on glucose for energy, ...

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

Menée sur 37 patients atteints d'un adénocarcinome canalaire du pancréas de stade avancé ou localement avancé, cette étude évalue la réponse à un traitement néoadjuvant combinant le cetuximab, la gemcitabine et une radiothérapie avec modulation d'intensité

Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma
• Annals of Oncology, sous presse, 2012 (résumé)

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Menée sur 37 patients atteints d'un adénocarcinome canalaire du pancréas de stade avancé ou localement avancé, cette étude évalue la réponse à un traitement néoadjuvant combinant le cetuximab, la gemcitabine et une radiothérapie avec modulation d'intensité

“Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma”

• Pipas, J. M.;Zaki, B. I.;McGowan, M. M.;Tsapakos, M. J.;Ripple, G. H.;Suriawinata, A. A.;Tsongalis, G. J.;Colacchio, T. A.;Gordon, S. R.;Sutton, J. E.;Srivastava, A.;Smith, K. D.;Gardner, T. B.;Korc, M.;Davis, T. H.;Preis, M.;Tarczewski, S. M.;MacKenzie, T. A.;Barth, R. J.

Background: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC.Experimental design: Treatment consisted of cetuximab load at 400 mg/m2 followed by cetuximab 250 mg/m2 weekly and gemcitabine 50 mg/m2 twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection.Results: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three ...

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

Menée sur 450 patients, cette étude montre qu'une leucémie myéloïde aiguë (LMA) et un syndrome myélodysplasique (SM) survenus après une radiothérapie sont semblables aux LMA et SM sporadiques mais diffèrent des LMA et SM consécutifs à une chimiothérapie ou à des traitements combinés

Acute Myeloid Leukemia and Myelodysplastic Syndromes After Radiation Therapy Are Similar to De Novo Disease and Differ From Other Therapy-Related Myeloid Neoplasms
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Menée sur 450 patients, cette étude montre qu'une leucémie myéloïde aiguë (LMA) et un syndrome myélodysplasique (SM) survenus après une radiothérapie sont semblables aux LMA et SM sporadiques mais diffèrent des LMA et SM consécutifs à une chimiothérapie ou à des traitements combinés

“Acute Myeloid Leukemia and Myelodysplastic Syndromes After Radiation Therapy Are Similar to De Novo Disease and Differ From Other Therapy-Related Myeloid Neoplasms”

• Nardi, Valentina;Winkfield, Karen M.;Ok, Chi Young;Niemierko, Andrzej;Kluk, Michael J.;Attar, Eyal C.;Garcia-Manero, Guillermo;Wang, Sa A.;Hasserjian, Robert P.

Purpose Therapy-related myeloid neoplasms (t-MN) represent a unique clinical syndrome occurring in patients treated with chemotherapy and/or external-beam radiation (XRT) and are characterized by poorer prognosis compared with de novo disease. XRT techniques have evolved in recent years and are associated with significantly reduced bone marrow exposure. The characteristics of post-XRT t-MN in the current era have not been studied.Patients and Methods We analyzed patients who developed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after XRT alone (47 patients) or cytotoxic chemotherapy/combined-modality therapy (C/CMT, 181 patients) and compared them with patients with de novo MDS or AML (222 patients). We estimated bone marrow exposure to radiation and compared the clinical, pathologic, and cytogenetic features and outcome of the XRT patients with the C/CMT patients and with patients with de novo MDS and AML.Results Patients with t-MN after XRT alone had superior ...
Cytogenetics, Not Just Previous Therapy, Determines the Course of Therapy-Related Myeloid Neoplasms
• Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)

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Menée sur 450 patients, cette étude montre qu'une leucémie myéloïde aiguë (LMA) et un syndrome myélodysplasique (SM) survenus après une radiothérapie sont semblables aux LMA et SM sporadiques mais diffèrent des LMA et SM consécutifs à une chimiothérapie ou à des traitements combinés

“Cytogenetics, Not Just Previous Therapy, Determines the Course of Therapy-Related Myeloid Neoplasms”

• Larson, Richard A.

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

Mené sur 559 patients atteints d'un cancer primitif de l'estomac de stade T3 avec ou sans envahissement ganglionnaire (durée médiane de suivi : supérieure à 10 ans), cet essai de phase III évalue, du point de vue de la survie globale et de la survie sans récidive, l'efficacité et la toxicité d'une chimioradiothérapie adjuvante par fluorouracile-leucovorine par rapport à une résection chirurgicale seule

Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 559 patients atteints d'un cancer primitif de l'estomac de stade T3 avec ou sans envahissement ganglionnaire (durée médiane de suivi : supérieure à 10 ans), cet essai de phase III évalue, du point de vue de la survie globale et de la survie sans récidive, l'efficacité et la toxicité d'une chimioradiothérapie adjuvante par fluorouracile-leucovorine par rapport à une résection chirurgicale seule

“Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection”

• Smalley, Stephen R.;Benedetti, Jacqueline K.;Haller, Daniel G.;Hundahl, Scott A.;Estes, Norman C.;Ajani, Jaffer A.;Gunderson, Leonard L.;Goldman, Bryan;Martenson, James A.;Jessup, J. Milburn;Stemmermann, Grant N.;Blanke, Charles D.;Macdonald, John S.

Purpose Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses.Patients And Methods In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy.Results Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from ...
Adjuvant Therapy for Gastric Cancer: Revisiting the Past to Clarify the Future
• Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)

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Mené sur 559 patients atteints d'un cancer primitif de l'estomac de stade T3 avec ou sans envahissement ganglionnaire (durée médiane de suivi : supérieure à 10 ans), cet essai de phase III évalue, du point de vue de la survie globale et de la survie sans récidive, l'efficacité et la toxicité d'une chimioradiothérapie adjuvante par fluorouracile-leucovorine par rapport à une résection chirurgicale seule

“Adjuvant Therapy for Gastric Cancer: Revisiting the Past to Clarify the Future”

• Brooks, Gabriel A. ; Enzinger, Peter C. ; Fuchs, Charles S.