Mené sur 25 patients atteints d'un cancer du poumon non à petites cellules de stade localement avancé (durée médiane de suivi : 13 mois), cet essai de phase I évalue, du point de vue des événements indésirables, la toxicité d'une protothérapie hypofractionnée avec escalade de doses

Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer

Gomez, Daniel R. ; Gillin, Michael ; Liao, Zhongxing ; Wei, Caimiao ; Lin, Steven H. ; Swanick, Cameron ; Alvarado, Tina ; Komaki, Ritsuko ; Cox, James D. ; Chang, Joe Y.

Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, [...]

Menée sur 916 patients atteints d'un cancer de la prostate et présentant des métastases après un premier traitement par prostatectomie radicale ou radiothérapie (durée médiane de suivi : 33 mois), cette étude évalue la survie spécifique des patients en fonction du traitement reçu

Cancer-specific Survival After Metastasis Following Primary Radical Prostatectomy Compared with Radiation Therapy in Prostate Cancer Patients: Results of a Population-based, Propensity Score–Matched Analysis

Yu-Hsuan Joni, Shao ; Sung, Kim ; Dirk, F. Moore ; Weichung, Shih ; Yong, Lin ; Mark, Stein ; Isaac Yi, Kim ; Grace, L. Lu-Yao

Background : Data regarding the difference in the clinical course from metastasis to prostate cancer–specific mortality (PCSM) following radical prostatectomy (RP) compared with radiation therapy (RT) are lacking. Objective : To examine the association between primary treatment modality and prostate cancer–specific survival (PCSS) after metastasis. Design, setting, and participants : We used the Surveillance Epidemiology and End Results–Medicare linked database from 1994 to 2007 for patients [...]

Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé MK-1775, un inhibiteur de la kinase WEE1

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single Agent Anticancer Therapy

Guertin, Amy D ; Li, Jing ; Liu, Yaping ; Hurd, Melissa S. ; Schuller, Alwin G. ; Long, Brian ; Hirsch, Heather A. ; Feldman, Igor ; Benita, Yair ; Toniatti, Carlo ; Zawel, Leigh ; Fawell, Stephen E. ; Gilliland, Gary ; Shumway, Stuart D

Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We demonstrate that MK-1775, a potent and selective ATP-competitive inhibitor [...]

Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale de nanoparticules magnétiques enrichies en curcumine pour le traitement d'un cancer du pancréas

Novel Curcumin Loaded Magnetic Nanoparticles for Pancreatic Cancer Treatment

Yallapu, Murali M ; Ebeling, Mara C ; Khan, Sheema ; Sundram, Vasudha ; Chauhan, Neeraj ; Gupta, Brij K ; Puumala, Susan E ; Jaggi, Meena ; Chauhan, Subhash C.

Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has demonstrated potent anti-cancer and cancer prevention activity in a variety of cancers. However, the clinical translation of curcumin has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics and poor bioavailability. To address these clinically relevant issues, we have developed a novel curcumin loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have [...]

Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé PG545, un inhibiteur de l'angiogenèse et de l'héparanase, pour le traitement d'un adénocarcinome canalaire du pancréas

PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer

Ostapoff, Katherine T ; Aswasthi, Niranjan ; Cenik, Bercin Kutluk ; Hinz, Stefan ; Dredge, Keith ; Schwarz, Roderich E ; Brekken, Rolf A

Aggressive tumor progression, metastasis and resistance to conventional therapies lead to an extremely poor prognosis for pancreatic ductal adenocarcinoma (PDAC). Heparanase, an enzyme expressed by multiple cell types including tumor cells in the tumor microenvironment, has been implicated in angiogenesis and metastasis, and its expression correlates with decreased overall survival in PDAC. We evaluated the therapeutic potential of PG545, an angiogenesis and heparanase inhibitor, in [...]

Cet article passe en revue les perspectives offertes par les connaissances sur des mécanismes d'hypoxie et de signalisation Notch pour le développement de traitements du cancer de la prostate

Hypoxia, notch signalling, and prostate cancer

Marignol, Laure ; Rivera-Figueroa, Karla ; Lynch, Thomas ; Hollywood, Donal

The notch signalling pathway is involved in differentiation, proliferation, angiogenesis, vascular remodelling, and apoptosis. Deregulated expression of notch receptors, ligands, and targets is observed in many solid tumours, including prostate cancer. Hypoxia is a common feature of prostate tumours, leading to increased gene instability, reduced treatment response, and increased tumour aggressiveness. The notch signalling pathway is known to regulate vascular cell fate and is responsive to [...]

Cet article passe en revue les enjeux associés à la prise en charge des effets indésirables associés aux thérapies ciblées anticancéreuses

Understanding, recognizing, and managing toxicities of targeted anticancer therapies

Dy, Grace K. ; Adjei, Alex A.

Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main [...]

Cet article passe en revue les travaux récents permettant de rendre compte des résultats cliniques décevants des essais ayant évalué un traitement anti-angiogénique dans les tumeurs solides

Anti-angiogenesis in cancer therapy: Hercules and hydra

Bellou, S. ; Pentheroudakis, G. ; Murphy, C. ; Fotsis, T.

Solid tumours initiate angio genesis to support their growth by producing growth factors such as VEGF. Depriving the tumour of the excessive vessels that support its growth became the target for developing anti-angiogenic agents that could provide, in combination with chemotherapy, improved anti-cancer treatment. Naturally most agents targeted VEGF and its signalling cascades. Almost 10 years have lapsed since the first anti-angiogenic drug approved by the FDA in 2004 (a humanized antibody [...]

Menée sur 40 patients atteints d'une leucémie myéloïde chronique en phase chronique sans maladie résiduelle minimale détectable pendant au moins deux ans, cette étude évalue la faisabilité et l'efficacité d'une interruption de l'imatinib accompagnée de la recherche régulière d'une récidive moléculaire

Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study

Ross, David M. ; Branford, Susan ; Seymour, John F. ; Schwarer, Anthony P. ; Arthur, Christopher ; Yeung, David T. ; Dang, Phuong ; Goyne, Jarrad M. ; Slader, Cassandra ; Filshie, Robin J. ; Mills, Anthony K. ; Melo, Junia V. ; White, Deborah L. ; Grigg, Andrew P. ; Hughes, Timothy P.

Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional Q-PCR on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months the actuarial estimate of stable treatment-free remission was 47.1%. Most [...]

Mené sur 61 patients atteints d'un lymphome diffus récidivant à grandes cellules B, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité de l'ofatumumab en remplacement du rituximab dans les protocoles de deuxième ligne après l'échec d'un traitement R-CHOP

Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma

Matasar, Matthew J. ; Czuczman, Myron S. ; Rodriguez, Maria Alma ; Fennessy, Michael ; Shea, Thomas C. ; Spitzer, Gary ; Lossos, Izidore S. ; Kharfan-Dabaja, Mohamed A. ; Joyce, Robin ; Fayad, Luis ; Henkel, Kristen ; Liao, Qiming ; Edvardsen, Klaus ; Jewell, Roxanne C. ; Fecteau, Doug ; Singh, Rajendra P. ; Lisby, Steen ; Moskowitz, Craig H.

Standard treatment for transplant-eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL) consists of rituximab and platinum-based chemotherapy, either ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP), with autologous transplant consolidation for those with chemosensitive disease. Nonetheless, outcomes are suboptimal for patients failing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We performed a [...]

Menée sur 33 patients atteints d'un mélanome métastatique et non résécable des muqueuses, cette étude rétrospective analyse l'efficacité et la toxicité de l'ipilimumab

Ipilimumab for Patients With Advanced Mucosal Melanoma

Postow, Michael A. ; Luke, Jason J. ; Bluth, Mark J. ; Ramaiya, Nikhil ; Panageas, Katherine S. ; Lawrence, Donald P. ; Ibrahim, Nageatte ; Flaherty, Keith T. ; Sullivan, Ryan J. ; Ott, Patrick A. ; Callahan, Margaret K. ; Harding, James J. ; D'Angelo, Sandra P. ; Dickson, Mark A. ; Schwartz, Gary K. ; Chapman, Paul B. ; Gnjatic, Sacha ; Wolchok, Jedd D. ; Hodi, F. Stephen ; Carvajal, Richard D.

The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. [...]

Cet article passe en revue les travaux récents sur les combinaisons de nouveaux traitements (ipilimumab, vermurafenib, dabrafenib, trametinib) pour les patients atteints d'un mélanome avec mutations du gène BRAF

Ipilimumab, Vemurafenib, Dabrafenib, and Trametinib: Synergistic Competitors in the Clinical Management of BRAF Mutant Malignant Melanoma

Luke, Jason J. ; Hodi, F. Stephen

There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T-lymphocyte antigen-4 blockade, with ipilimumab, and targeting of BRAFV600, with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. [...]

Cet article passe en revue les travaux récents sur la survenue de seconds cancers chez les patients atteints d'un mélanome traité par inhibiteur de BRAF

Paradoxical oncogenesis - the long-term effects of BRAF inhibition in melanoma

Gibney, Geoffrey T. ; Messina, Jane L. ; Fedorenko, Inna V. ; Sondak, Vernon K. ; Smalley, Keiran S. M.

The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps. In [...]

A partir d'une revue systématique de la littérature publiée entre 1993 et 2012 (9 études), cette étude évalue, du point de vue de la survie à long terme, l'intérêt d'une prostatectomie radicale et d'un curetage ganglionnaire pelvien, combinés ou non à une radiothérapie et/ou à un traitement anti-androgénique, chez les patients atteints d'un cancer de la prostate avec envahissement ganglionnaire

The Role of Radical Prostatectomy and Lymph Node Dissection in Lymph Node–Positive Prostate Cancer: A Systematic Review of the Literature

Georgios, Gakis ; Stephen, A. Boorjian ; Alberto, Briganti ; Steven, Joniau ; Guram, Karazanashvili ; Jeffery, Karnes ; Agostino, Mattei ; Shahrokh, F. Shariat ; Arnulf, Stenzl ; Manfred, Wirth ; Christian, G. Stief

Context : Because pelvic lymph node (LN)-positive prostate cancer (PCa) is generally considered a regionally metastatic disease, surgery needs to be better defined. Objective : To review the impact of radical prostatectomy (RP) and pelvic lymph node dissection (PLND), possibly in conjunction with a multimodal approach using local radiotherapy and/or androgen-deprivation therapy (ADT), in LN-positive PCa. Evidence acquisition : A systematic Medline search for studies reporting on treatment [...]

Mené sur 46 patientes atteintes d'un cancer du col de l'utérus de stade Ib2-IVa, cet essai de phase II évalue la faisabilité d'un protocole de chimiothérapie "dose dense" par carboplatine-paclitaxel avant une chimioradiothérapie radicale

A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer

McCormack, M. ; Kadalayil, L. ; Hackshaw, A. ; Hall-Craggs, M. A. ; Symonds, R. P. ; Warwick, V. ; Simonds, H. ; Fernando, I. ; Hammond, M. ; James, L. ; Feeney, A. ; Ledermann, J. A.

Background : We investigated the feasibility of dose-dense neoadjuvant chemotherapy (NACT) with paclitaxel and carboplatin before radical chemoradiation (CRT) and assessed the response rate to such a regimen. Methods : CxII is a single-arm phase II trial of 46 patients, with locally advanced cervical cancer (stage Ib2-IVa). Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg m−2) weekly for six cycles followed by CRT (40 mg m−2 of weekly cisplatin, 50.4 Gy, 28 fractions plus [...]

A partir d'une revue systématique de la littérature portant sur des essais de phase II dans les sarcomes avancés des tissus mous (53 articles identifiés), cette étude évalue la qualité méthodologique de ces essais du point de vue de la pertinence du critère principal de jugement utilisé

Activity endpoints reported in soft tissue sarcoma phase II trials: Quality of reported endpoints and correlation with overall survival

Penel, Nicolas ; Cousin, Sophie ; Duhamel, Alain ; Kramar, Andrew

Background Despite extensive research over the past 3 decades, few investigational drugs are considered as promising and these drugs failed to improve overall survival. Therefore we performed a systematic review of the literature to improve our understanding of the reasons that explain these failures. Methods We reviewed 53 phase II trial reports that investigated new treatments in patients with advanced soft tissue sarcoma from 1999 to 2011. We critically reviewed the selected primary endpoint [...]