Summary - Brain Mets 2018brain-mets.com/files/31/recueil-21.pdf · 3 Opening Speech Approximately 20% of patients with cancer develop brain metastases. Some evidence indicates that

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Opening Speech..............................................................2

Speakers................................................................................5

Scientific Program.........................................................9

Abstracts............................................................................13

Summary

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Opening Speech Approximately 20% of patients with cancer develop brain metastases. Some evidence indicates that as techniques for treating systemic tumors improve, the incidence of brain metastases, sequestered as they are behind the blood-brain barrier, is increasing.

Indeed, the brain is regarded as a sanctuary site for metastatic tumor cells where they exist partially protected from drugs by the blood-tumor barrier. Model systems for brain metastasis is an emerging area of interest in organ-specific metastasis research and are now yielding mechanistic insights into the roles of angiogenesis, energy metabolism, growth factors signaling pathways, and dormancy.

The diagnostic and therapeutic approach depends on the number and location of brain lesions and the stage of the primitive cancer. Patients with brain metastases are rarely cured. However, appropriate treatment can improve both the quality and duration of the patient’s life. Treatment management of brain metastasis is constantly evolving and emerging therapeutic strategies associating novel radiation therapy protocol and new pharmacologic agents are booming in the literature, which witnesses a massive interest in this research area.

In order to make a point on the latest advances and researches in this promising field, Canceropôle PACA gather during this specific thematic meeting the best world known specialists of the domain under the direction of Prof. Henry Dufour and Dr Philippe Métellus, from the Neurosurgery Department at the University Hospital La Timone in Marseille.

Dr Philippe Métellus Service de Neurochirurgie, Hôpital La Timone, Marseille, France

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Opening Speech

Cancéropôles were created in 2003 as essential components of the first “fight against cancer” plan, spearheaded by the installation of the French National Cancer Institute (“Institut National du Cancer”, Inca). The mission of Cancéropôles is to build regional networks between all actors that contribute to research in oncology, from basic to clinical and socio-economical research. Through initiatives that support a multi-disciplinary approach and the association of expertises and competencies either in platforms or in scientific projects, the goal is to accelerate the rate of new discoveries about the many aspects of cancer biology, epidemiology and care as well as their translation into benefits and improved outcomes for patients.

Since its creation, the Cancéropôle PACA that unites scientists and healthcare professionals from south-eastern France, mainly in the Marseilles and Nice metropolitan areas, has succeeded in many of these endeavours. In 2011, the Cancéropôle PACA underwent a successful evaluation by AERES, and was subsequently recognized again by INCa for an additional 3 year term (2011-2014). The Cancéropôle PACA receives financial support from INCa as well as from the PACA Regional Authority (“Conseil Régional PACA”)

Bringing together scientists from inside as well as outside the Cancéropôle PACA to share their knowledge is an essential “tool” to favour the emergence of new collaborative projects. Each year, the Cancéropôle PACA contributes to the organization of several meetings, seminars and congress within its geographical area, often as a partner to other institutions or scientific societies, and supports young PACA investigators to attend and present their work at meetings and seminars outside its territory. It is our goal that in addition to the Annual Cancéropôle PACA meeting that is traditionally held at the Conseil de Région and offers an opportunity to present the achievements of local investigators, the Cancéropole PACA acts as the main organizer of a yearly seminar dealing with a highly specific topic, in order to bring together external and internal experts. In 2011, the selected topic was “Brain Metastases: Emerging Therapeutic Strategies and Opportunities in Basic & Translational Research”.

In line with the general objectives and missions of Cancéropôle PACA, the meeting that you are now attending encompasses all fields of biology and medicine, from basic research to clinical research. Its brings together some of the best experts in the field, scientists and healthcare professionals from various specialties, at a time when new therapeutic tools become available for what remains one of the difficult to deal with issue in oncology.

The Cancéropôle PACA coordination that has invested a lot of time and energy in organizing this event, as well as the local organizers and I, expect that this meeting will provide an exceptional forum for discussion and exchange, and fuel new initiatives.

I would like to thank all of those who contributed their time and energy, as well as all institutions and private sponsors who supported the organization of this main event.

I wish you a fruitful and enjoyable stay in Marseilles.

Christian Chabannon, MD, Ph.D Director. Cancéropôle PACA

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Speakers

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Speakers

Hidefumi Aoyama, Department of radiology, Niigata University,Niigata, Japan

David Azria, Dép. d’Oncologie Radiothérapie, CRLC Val d’Aurelle, Montpellier, France

Fabrice Barlési, Service d’Oncologie Multidisciplinaire, Hôpital Nord, Marseille, France

Benjamin Besse, Dép. d’Oncologie Thoracique, Institut de Cancérologie Gustave Roussy, Villejuif, France

Steven Brem, Dept of Neurosurgical Oncology, Brain Tumor Center, Philadelphia, USA

Antoine Carpentier, Service de Neurologie, Hôpital Avicenne, Bobigny, France

Olivier Chinot, Service de Neuro-oncologie, Hôpital La Timone, Marseille, France

Frédéric Dhermain, Département de Radiothérapie, Institut Gustave Roussy, Villejuif, France

Henry Dufour, Chef du Service de Neurochirurgie, Hôpital La Timone, Marseille, France

Isaiah J. Fidler, MD Anderson Cancer Center, Dept of Cancer Biology, Houston, TX, USA

Dominique Figarella-Branger, Service d’Anatomo-pathologie, Hôpital La Timone, Marseille, France

Denys Fontaine, CHU Pasteur, Service de Neruochirurgie, Nice, France

Anthony Gonçalves, Oncologie Médicale, CLCC, Institut Paoli-Calmettes, Marseille, France

Deepak Khuntia, Western Radiation Oncology, San José, CA, USA

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Bodo Lippitz, Gamma Knife Centre, Bupa Cromwell Hospital, London, UK (Elekta)

Emilie Le Rhun, Dép. de Cancérologie Sénologique, Centre Oscar Lambret, Lille, France

Nancy U. Lin, Dana-Farber Cancer Insitute, Harvard Medical School, Boston, MA, USA

Philippe Métellus, Service de Neurochirurgie, Hôpital La Timone, Marseille, France

Xavier Muracciole, Service de Radiothérapie, Hôpital La Timone, Marseille, France

Laëtitia Padovani, Service de Radiothérapie, Hôpital La Timone, Marseille, France

Jean Régis, Service de Neurochirurgie Stéréotaxique et Fonctionnelle, Hôpital La Timone, Marseille, France

Agnès Richard-Tallet, Radiothérapie, CLCC, Institut Paoli-Calmettes, Marseille, France

Daniele Rigamonti, Johns Hopkins Hospital Dept of Neurosurgery and Radiosurgery, Baltimore, MD, USA

Rolf Staehelin, (Varian)

Jean-Philippe Spano, Département d’Oncologie Médicale, Hôpital La Pitié-Salpêtrière, Paris, France

Sophie Taillibert, Service de neurologie, Hôpital Pitié Salpétrière, Paris, France

Ruud Wiggenraad, RC West Hospital, The Hague, The Netherlands (Brainlab)

David Zagzag, Dept of Neuropathology, New York University School of Medicine, New York, USA

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ScientificProgram

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Scientific ProgramFriday September 16, 201107.45 Welcome to participant - Coffee08.20 Welcome Address, Henry Dufour & Christian Chabannon08.30 Introduction, Philippe Métellus & Anthony Gonçalves

09.00 Opportunities for Basic and Translational Research CHAIRPERSONS: Dominique Figarella-Branger & David Zagzag 09.00 - 09.45 The biology and therapy of brain cancer metastasis, Isaiah J. Fidler09.45 – 10.30 Hypoxia, angiogenesis and blood brain barrier, David Zagzag10.30 Coffee break

10.45 Surgical Management of Brain Metastases CHAIRPERSONS: Daniele Rigamonti & Henry Dufour10.45 – 11.15 Surgical management of brain metastases: the place of local treatment, Steven Brem

11.30 Radiosurgical Strategies CHAIRPERSONS: Philippe Métellus & Deepak Khuntia11.30 – 12.00 Histological differences in outcomes of radiosurgical treatment of brain metastasis: a classification and tree analysis, Daniele Rigamonti12.15 – 12.35 A Rationale for on demand radiosurgery in Brain Metastases, Jean Régis12.45 Lunch break

13h30 Symposia from the Industry 13.30 Gamma Knife treatment of Brain Metastases : Track Record and Specific Features, Bodo Lippitz 13.45 Emerging Clinical Tools for Image Guided High Precision Radiosurgery in the Brain, Rolf Staehelin14.00 Local control after SRT for brain metastases, Ruud Wiggenraad14.15 Discussion

14.30 Radiotherapy CHAIRPERSONS: Xavier Muracciole & Hidefumi Aoyama14.30 – 15.00 Role of Whole Brain Radiotherapy and Novel Strategies for Overcoming Neurocognitive Decline, Deepak Khuntia15.15 – 15.45 Lessons from the EORTC Trial, Denys Fontaine16.00 Coffee break

16.15 Monitoring of Brain Metastases and Assessment of Therapeutic Response CHAIRPERSON: Laëtitia Padovani & Daniele Rigamonti16.15 – 16.35 Lessons from primary tumors, Olivier Chinot

16.45 Neurocognitive Function in Brain Metastases CHAIRPERSONS: Deepak Khuntia & Agnès Richard-Tallet16.45 – 17.05 Is systemic anti-cancer therapy neurotoxic? Does «chemobrain» exist? And should we rename it? Sophie Taillibert17.15 – 18.00 Neurocognitive decline WBRT vs. Intracranial progression, Hidefumi Aoyama20.00 Gala dinner

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Saturday September 17, 201108.30 From Chemotherapy to Targeted Therapies - Part 1 CHAIRPERSONS: Isaiah J. Fidler & Anthony Gonçalves08.30 – 09.00 New pharmacological agents in brain metastases from breast cancer: a comprehensive overview, Nancy U. Lin09.15 – 09.35 Antiangiogenics in brain metastasis, Benjamin Besse09.45 – 10.05 DNA Repair inhibition and tumor cell radiosensitization, David Azria10.15 Coffee break

10.30 From Chemotherapy to Targeted Therapies - Part 2 CHAIRPERSONS: Nancy U. Lin & Fabrice Barlési 10.30 – 10.50 Place of TKI in the managment of brain metastases of lung cancer, Antoine Carpentier11.00 – 11.20 Leptomeningeal brain metastasis, Emilie Le Rhun

11.30 Clinical case studies: Interactive Session CHAIRPERSON: Frédéric Dhermain & Jean-Philippe Spano 12.45 Conclusion, Philippe Métellus & Anthony Gonçalves13.00 Buffet lunch

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Abstracts

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The Biology and Therapyof Brain Cancer Metastasis

Isaiah J. FidlerDepartment of Cancer Biology, Metastasis Research Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

Despite improvements in surgical techniques, general patient care, and local and systemic adjuvant therapies, most deaths from cancer still result from the progressive growth of metastases that are resistant to conventional therapies. Tumor cells are genetically unstable and, consequently, neoplasms are biologically heterogeneous. The process of tumor metastasis is highly selective consisting of a series of sequential, interrelated steps. The outcome of metastasis depends on multiple interactions of selected metastatic cells (“seed”) with a specific organ microenvironment (“soil”) which tumor cells can exploit. A clear example of these interactions is the biology of brain metastasis. In the USA, more than 40% of cancer patients develop fatal brain metastasis. With improved local control and therapy of metas-tasis to visceral organs, the morbidity and mortality due to late diagnosed brain metastasis is projected to rise. The median survival for untreated patients is 1-2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The resis-tance of tumor cells growing in the brain parenchyma to chemotherapy has been attributed to the inability of circulating chemothe-rapeutic drugs to penetrate the blood-brain barrier. Recent data, however, revealed that tumor cells growing in the brain parenchyma release VEGF that lead to increased vessel permeability. Taken together with clinical observations that brain metastases in patients are often diagnosed as lesions surrounded by edema, these data raise the possibility that alternate mechanisms underlie the drug resistance of brain metastasis. Histological examinations of clinical specimens of human brain metastases and experimental murine brain metastases reveal that the lesions are surrounded and infiltrated by reactivated astrocytes that express glial fibrillary acidic protein. Astrocytes contribute to cerebral homeostasis, support immune defense in the brain and protect neuronal cells from waste products, and damage from hypoxia. Thus, astrocytes protect neurons from alterations in homeostasis. Because metastases develop when tumor cells exploit or usurp the homeostatic mechanisms of their host, we became intrigued by the possibility that tumor cells can exploit the cyto-protective proper-ties of astrocytes for protection from apoptosis induced by chemotherapeutic drugs. Co-culture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts) led to upregu-lation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of upregulation directly correlated with increased resistance to all tested chemotherapeutic agents. The upregulation of the survival genes and consequent resistance are dependent on direct contact between the astrocytes and tumor cells through gap junction communications, and is therefore transient. Knocking down these genes with specific siRNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that astrocytes influence the biological behavior of tumor cells and provide a new concept for the design of therapy for the most fatal aspect of cancer.

Abstract 1

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Hypoxia, angiogenesis and blood brain barrier

David ZagzagDepartment of Neuropathology, New York University School of Medicine, New York, USA

Hypoxia has long been known as a major stimulator of angiogenesis in brain tumors. The transcription factor hypoxia inducible factor (HIF)-1 induces expression of many genes under the regulation of hypoxia response elements (HREs). This process triggers the upregulation of multiple pro-angiogenic factors such as vascular endothelial growth factor, (VEGF). The expression level of HIF-1α and VEGF in brain tumors is intense around areas of necrosis suggesting that this pattern of expression of HIF-1α and VEGF is modulated by tumor oxygenation. Angiogenesis is the capillary sprouting from pre-existing host tissue. The permeability of newly formed vascular channels compa-red with that of mature capillaries is increased. Normal capillaries of the brain maintain the integrity of the blood brain barrier, but the blood vessels of experimental and human brain tumors are structurally altered and have increased capillary permeability. Angiogenesis has now been recognized as a highly complex spectrum of events. Currently, at least four other distinct mechanisms of vascularization in brain tumors have been identified: 1) vascular co-option, 2) vasculogenesis, 3) vascular mimicry, and 4) tumor cell-endothelial cell transdifferentiation. These mechanisms do not exist independently of one another, but are interlinked and controlled, at least in part, by similar processes. Although outcomes have been generally encouraging with anti-angiogenic therapy, concerns over resistance to therapy, rebound revascularization, and shifts to a more invasive phenotype have all emerged. Regardless, anti-angiogenic therapy is undoubtedly an important step forward in the development of effective targeted therapy. It is clear that neovascularization is more complex than angiogenesis alone. We are confident that a thorough understanding of the contributing molecular processes that control the five moda-lities we have reviewed should help overcome the treatment resistance that characterizes these tumors.

Abstract 2

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Surgical management of brain metastases: the place of local treatment

Steven BremDept of Neurosurgical Oncology, Brain Tumor Center, Philadelphia, USA

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Abstract 3

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Histological differences in outcomes of radiosurgical treatment of brain metastases: a classification and tree analysis.

Daniele RigamontiJohns Hopkins Hospital Department of Neurosurgery and Radiosurgery, Baltimore, USA

The usefulness of Stereotactic radiosurgery (SRS) in the management of cerebral metastases has been established by several large clinical series. What is less clear is if and how histology plays a role in the outcome of SRS treatment. Several very useful grading scales have been developed over the years to help determining the prognosis of patients with cerebral metas-tases that are undergoing SRS. Karnofsky performance scales (KPS), age, number of lesions, status of extracranial disease seem to influence the outcome of most of the patients. Recent publications have suggested that histology is relevant in this regard. Our experience comprises 1318 patients treated at Johns Hopkins Hospital (238 patients: between 2004-2007) and at Miami neuroscience center (1080 patients: between 1990 and 2009). The patient population consisted of metastasis from Non small cell lung cancer(NSCLC) in 480 (36.45%) patients with MS of 7.14mths, breast cancer in 301(22.85%) patients with MS of 9.08mths, Melanoma in 163(12.38%) patients with MS of 5.03mths, colorectal cancer in 69(5.24%) patients with MS of 4.05mths, renal cell cancer in 71(5.39%) patients with MS of 8.26mths, small cell cancer in 64(4.86%) patients with MS of 4.57mths and miscellaneous in 169(12.83%) patients with MS of 7.14mths. Overall Cox proportional hazard model revealed KPS (HR 1.03), age (HR 1.01), number of lesions (HR 1.03) and male gender (HR 1.3) to be independent predictors of mortality even when used as continuous variables. Based on CART analysis we classified our data into stage 1A1 (KPS>70, lesions<3, age<65: mortality: 72%, HR 0.65, survival:10.82 months, stage 1A2 (KPS>70, lesions<3, age>65: mortality: 62%, HR 0.97, survival 8.26 months), stage1B(KPS>70, lesions>3, mortality:89%, HR 1.2, survival 6.41mths), Stage2 (KPS<70: mortality: 93%, HR 1.78, survival 3.42mths )(p<0.001). Survival significantly correlated with decreasing class, p<0.001. Stratified Cox regression revealed that this model was applicable to Breast, NSCLC, and others. In patients with melanoma survival was independent of age but adversely effected with >3 lesions and KPS<70. Whereas we found that in Renal, colorectal and small cell lung cancer KPS>70 was the only predictor of survival. Our experience, therefore, both corrobo-rates the usefulness of current grading scales and indicates some of their shortcomings, suggesting that they do not apply to all types of tumors. Such findings are not unexpected and point to several factors that in different degree contribute to outcome. Historical long-term sur-vival data clearly established that some cancers are associated with a more indolent course than others. The tendency of a primary cancer to metastasize is unquestionably dependent on the histology of the primary. The tropism to the brain varies between different histologies and within the same histology between the subtypes. The survival and growth of a cerebral metastasis greatly depends on its ability to parasitize blood supply from the surrounding brain parenchyma: there is new experimental data showing different angiogenic potential of different types of tumors. The general status of the patient at the time of development of cerebral metastases that is reflected in the critical important KPS depends on the existing tumor load. Cancers that before metastasizing to the brain have metastasized liver and lungs, because of the loca-tion of the primary (i.e. Colon-rectal) are more likely to develop a cerebral metastasis in a patient that is sicker than say a non-small cell lung cancer. Lastly recent evidence confirms that histological subtypes of the same primary are characterized by different aggressiveness. The most dramatic example is the dismal survival in patients presenting with brain metastases from triple negative breast cancer.

Abstract 4

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What Rational for On Demand Radiosurgery in Brain Metastases ?

Jean Régis, Xavier MuraccioleStereotactic & Functional Neurosurgery Department,Aix-Marseille Univ, Timone University Hospital, AP-HM, France

Radiosurgical (RS) series with sufficient marginal dose without WBRT are reporting local control rates equal or superior to resec-tion plus WBRT (Muacevic08). The association of WBRT to radiosurgery is reducing slightly but significantly the probability of new brain metastases (from 66% to 42% in Ayoama07). This benefit is clearly shown only for Lung origin. The selection of the therapeutic strategy must take into account the origin of the primary cancer (Golden08). Thus, we are not proposing WBRT when the primary is a melanoma or a kidney cancer (Powel08). Best indications of RS are small nodular metastases (Shiau97). Many of the neurosurgical teams with availability of human and technical resources for good quality radiosurgery are moving toward a « on demand » radiosurgical strategy consisting in the RS treatment of the BM without WBRT, a cautious MR follow up (every 3months), the repeatition of RS as frequently as necessary and a salvage WBRT only in cases of very numerous lesions or carcinomatous meningitis (Linskey09). This approache is supported by the absence of chances loss in thoses receiving salvage WBRT only compared to those exposed to upfront WBRT (Sneed99). The advantage is to reduce the use of WBRT and then the neurocognitive toxicity, the risk of radionecroses (Xu07), the cost (Aoyama07) and the requirement for chemo stop (Larson10). The toxicity of radiosurgery is very lo even in highly functional areas (Dea10).

The level of evidence for neurotoxicity specialy neurocognitive and mnesic toxicity of WBRT even on the short term is growing steadly (Welzel07, Slotman07, Chang09, Douw09). The dramatic improvement of the safety efficacy of treatments in oncology in general are providing us with much more long survival and must lead us to be more concerned about iatrogenic long term toxicity and quality of life worsening. If the number of lesion operated by radiosurgery is increase the risk of appearance of new BM (Sawrie08) it does not per se reduce the survival (Larson03, Chang10). As a matter of fact, the activity of RS for BM is increasing dramaticaly nowadays (roughly 600 operated by Gamma Knife versus 100 resected in Timone in 1 year). However, several questions related to the indications of this approach, the remaining role for associated treatments (WBRT) and the limit of application in cases of multiple lesions and or as a complement to a resection (Tumor Bed Radiosurgery) are also still a matter of debate.

Abstract 5

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The dandelion effect: Treat the whole lawn or weed selectively.

Deepak KhuntiaWestern Radiation Oncology, San José, CA, USA

Brain metastases represents a a very significant problem and is likely rising giving the improved longevity of cancer patients as well as improved imaging techniques for early detection. Whole brain radiation therapy (WBRT) has been the standard of care either alone or in conjunction with radiosurgery or surgical resection. However, its routine use has been called into question despite the lack of significant level 1 evidence supporting this evolution. The main concerns of practicing oncologists has been the fear of worsening cognitive deficits. Here we will discuss strategies incorporated for prevention of neurocognitive decline. Prevention can come in the form of chemoprevention as well as advanced radiation techniques to spare different structures of the brain (such as the hippocampus).

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Lessons from the EORTC Trial

Riccardo Soffietti 1, François Fauchon 2, Denys Fontaine 21. Division of Neuro-Oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Torino, Italy2. CHU Pasteur, Service de Neurochirurgie, Nice, France

The role of adjuvant whole brain radiotherapy (WBRT) after surgery or radiosurgery of a limited number of brain metastases has been debated for long time. Reasons for WBRT are as follows: WBRT destroys microscopic metastatic deposit at original tumor site or at distant intracranial locations; recurrent brain metastases present most commonly with symptomatic neurological deficit and/or neurocognitive decline; when adjuvant WBRT is omitted, there is an increased need for salvage treatments and it is not clearly defined their value in reversing the neurological symptoms/signs. Conversely, MRI has increased the chance of detecting small lesions and hy-pofractionated treatments (i.e. 30Gy/10 fractions) can be ineffective (especially in radioresistant tumors). Moreover, hypofractionated treatments carry a not negligeable risk of cognitive deficits, and this could be expecially true in long surviving patients (≥ 1 year). In an American phase III study adjuvant WBRT after surgery significantly reduces local and distant CNS relapses (18% versus 70 %) without improving overall survival and functionally independent survival. Similarly, in a Japanese phase III study adjuvant WBRT after radiosurgery improves local control and reduces the risk of new distant brain metastases without influencing overall survival. A recent EORTC phase III trial has confirmed that WBRT does not improve functionally independent and overall after either surgical resection or radiosurgery of 1-3 brain metastases in patients with stable/ absent systemic disease, while modestly improving progression-free survival by reducing the rate of both local and distant relapses in the brain. Moreover, WBRT may negatively impact some aspects of quality of life, even if these effects are transitory. In conclusion, the choice of observation with close monitoring with MRI (as done in the EORTC trail), instead of adjuvant WBRT, is not detrimental for survival and quality of life of patients, thus this is an option to be discussed with patients.

Abstract 7

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Lessons from primary tumors

Olivier ChinotService de Neuro-oncologie, Hôpital La Timone, Marseille, France

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Abstract 8

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Is Systemic Anti-Cancer therapy neurotoxic? Does “Chemobrain” exist? And should we rename It?

Sophie Taillibert 1, 2 1. AP-HP, Hôpital de la Salpétrière, Service de Neurologie Mazarin, F-75651, Paris, France 2. AP-HP, Hôpital de la Pitié-Salpétrière, Service de Radiothérapie, Paris, France.

Purpose The existence of “chemobrain” has become almost universally accepted, although the exact definition of this concept remains controversial. Data about the different types of cognitive impairment and their duration are not always consistent in the literature. We still do not know which drugs are responsible, which characteristics make patients vulnerable, and which biologic mechanisms are involved.

Summary The aim of this presentation is to provide an actualized definition of “chemobrain” including recent functional imaging data and to debate its controversial aspects. A better understanding of potential underlying mechanisms is needed. An updated explanation of these ones is discussed. This definition relies on evolving etiological hypotheses, each one representing a potential and emerging the-rapeutic option. This issue is of major clinical importance given the high incidence of breast cancer and the increasing survival rates of this patients secondary to the increased use of chemotherapy as adjuvant therapy and the increasing use of more aggressive dosing schedules. Better-designed future trials should lead to a better definition and understandingof “chemobrain” and to future therapies.

Keywords Breast cancer, chemobrain, chemotherapy, cognitive impairment, cognitive side-effects, neurotoxicity

Abstract 9

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Neurocognitive decline WBRT vs. Intracranial progression

Hidefumi AoyamaDepartment of Radiology, Niigata University, Niigata, Japan

The goals of treatment for brain metastases (BMs) include preservation of function and improvement of survival. Although whole brain radiotherapy (WBRT) has been a mainstay in the treatment of BMs, stereotactic radiosurgery (SRS) monotherapy has been in-creasingly used because of concern about the deterioration of neurocognitive function as a late adverse effect of WBRT. The results of 4 randomized controlled trials between focal treatment alone versus focal treatment combined with WBRT have shown, however, that SRS monotherapy significantly increases the risk of brain tumor recurrence (BTR) and that this increased risk of BTR may cause dete-rioration of neurocognitive function. We suggest identifying patients according to their risk of BTR when selecting treatment. Patients who have solitary BM with the absence of extracranial metastases may be indicated for SRS monotherapy given the lower risk of BTR compared with those having multiple BMs or extracranial metastases.

Abstract 10

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New Pharmacological Agents in Brain Metastases from Breast Cancer: A Comprehensive Overview

Nancy U. Lin,Dana-Farber Cancer Institute,Boston, USA

Brain metastases are diagnosed in 10-15% of patients with advanced breast cancer as a whole. However, the incidence of brain metastases is significantly higher in patients with HER2-positive and triple-negative breast cancer subtypes. While radiotherapy-based treatments are effective, an increasing number of patients are developing progression beyond radiation. In that setting, there is consi-derable debate about the optimal approach. Currently, no systemic therapies are approved for the treatment of breast cancer brain metastases. However, activity has been observed with a number of traditional cytotoxic chemotherapies, and there is new data suppor-ting the activity of targeted agents, alone, and in combination, in this setting. As a result, there is great interest in exploring systemic therapy as front-line treatment (i.e. in lieu of radiotherapy), in conjunction with radiation, or in a prevention setting. This talk will review the available data, discuss ongoing and planned clinical trials, and explore future directions.

Abstract 11

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Antiangiogenics in brain metastasis

Benjamin BesseInstitut Gustave Roussy, Department of Medicine, Villejuif, France.

The risk of cerebral haemorrhage in patients with brain is related to tumor type. The risk is higher in renal cell carcinoma (70%) or melanoma (40-50%) than for lung cancer (1%) or breast cancer (5%)(1). Drugs that target the VEGFR pathway, also known as antiangiogenic agents, had demonstrated activity in selected tumor type: bevacizumab in non small cell lung cancer, colo-rectal cancer, breast cancer and kidney cancer, sunitinib and sorafenib in renal cell carcinoma for example. Patients with central nervous system (CNS) metastases have until recently been routinely excluded from antiangiogenic trials, following a single case in 1997 of a 29-year-old patient with hepatocellular carcinoma (HCC) who experienced a fatal cerebral haemorrhage from a previously undiagnosed brain metastasis in a phase I study of bevacizumab. Thus, there are few data regarding safety and efficacy of antian-giogenic agents in patients with brain metastases. In a recent review, the risk of cerebral haemorrhage in patients treated with antiangiogenic agents was evaluated in 57 studies(2). In phase I studies, 2 patients experienced a cerebral haemorrhage out of 1755 patients enrolled (0.11%). In phase I and II studies that did not exclude patients with brain metastases, one case of cerebral haemorrhage was reported out of 524 patients (0.2%). Regarding 11 phase III studies (8 with bevacizumab, 2 with sunitinib and 1 with sorafenib), 5 patients developed a cerebral haemorrhage out of 5476 patients (0.1%). The role of brain radiotherapy in cerebral haemorrhage incidence was not reported. Another analysis addressed whether patients with CNS metastases were at increased risk of cerebral haemorrhage when treated with bevacizumab(3). The retrospective exploratory safety review of randomized controlled trials (n=8443) identified that 2.2% of patients had CNS metastases. The rate of cerebral haemorrhage in the bevacizumab-treated group was 3.3%, compared with 1.0% in the non-bevacizumab group. Mortality rates were similar between the bevacizumab and control arms. Nevertheless, these patients were highly selected since brain metastases was an exclusion criteria in most of these trials. The PASSPORT study specifically addressed bevacizumab safety in patients with NSCLC and previously-treated brain metastases(4). Of 115 enrolled patients, no (0%) episodes of Grade >2 CNS haemorrhage (95% CI, 0.0% to 3.3%) was reported. It should be highlighted that none of these patients had neurological symptoms at study entry and that all of them were treated with brain radiotherapy before bevacizumab treatment. In 321 patients with metastatic renal cell carcinoma and brain metastases enrolled in an open-label expanded access program, the safety profile of sunitinib was manageable. One case of cerebral haemorrhage was reported. Of 213 evaluable patients, 26 (12%) had an objective response(5). In a similar cohort of 2515 renal cell carcinoma patients treated with sorafenib (70 patients had brain metastases at baseline), there was less than 1% of cerebral haemorrhage. Objective responses of brain metastases during bevacizumab treatment were reported (6). Bevacizumab efficacy in non small cell lung cancer patients with untreated brain metastases is addressed in a ongoing phase II study (NCT00800202).

Abstract 12

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In conclusion, in these studies with selected patient population, patients with CNS metastases seem to be at a similar risk of developing a cerebral haemorrhage, independent of antiangiogenic therapy. Results from ongoing studies will provide further guidance regarding the use of antiangiogenic agents in patients with brain metastases. Treatment decisions should be driven by the benefit/risk assessment made by physicians for individual patients.

Reference List1. Carden CP, Larkin JM, Rosenthal MA. What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro Oncol 2008; 10(4):624-630.2. Carden CP, Larkin JM, Rosenthal MA. What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro Oncol 2008; 10(4):624-630.3. Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res 2010; 16(1):269-278.4. Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 2009; 27(31):5255-5261.5. Gore ME, Hariharan S, Porta C, Bracarda S, Hawkins R, Bjarnason GA et al. Sunitinib in metastatic renal cell carcinoma patients with brain metastases. Cancer 2011; 117(3):501-509.6. De Braganca KC, Janjigian YY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP et al. Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol 2010; 100(3):443-447.

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DNA Repair inhibition and tumor cell radiosensitization

David AzriaDépartement d’oncologie radiothérapie, CRLC Val d’Aurelle,Montpellier,France

PARP-1 is a key enzyme in the base excision repair (BER) pathway in higher eukaryotes which repairs both base damage and single strand breaks in DNA. Following exposure to ionizing radiation, substantial number of modified bases and single-strand DNA breaks (SSB) are formed and efficient repair of these lesions is essential for the maintenance of genome integrity. PARP inhibitors are able to potentiate radiation-induced cell killing during the S phase. Mechanistic studies have shown that this is due to the conversion of unrepaired SSB into lethal double-strand breaks (DSB) through their collision with incompletely stalled replication forks. The DSB repair pathways cannot repair all the DSB formed de novo during S phase leading to cell death. Other data showed that PARP inhibitors elicit radiosensitization in exponentially growing, while sparing quiescent-arrested cells. Other labs demons-trated the cytotoxic effect of the inhibitors when combined with chemical agents that generate DNA damage in many different cellular models including BRCA1/2-defective cells. In vivo studies have also been carried out using xenografted models of melanoma, glioblastoma, lymphoma, breast, head and neck and colorectal cancers. In all these studies, PARP inhibitors were found to enhance the cytotoxic effect of radiation or DNA-targeting drugs whose repair requires the excision of base damage (e.g. cisplatin, carboplatin, temozolomide). In addition, PARP-1 is an abundant nuclear enzyme that is activated primarily by DNA damage. Upon activation, the enzyme hydrolyzes NAD(+) to nicotinamide and transfers ADP ribose units to a variety of nuclear proteins, including histones and PARP-1 itself. This process is important in faci-litating DNA repair. However, excessive activation of PARP-1 can lead to significant decrements in NAD(+), and ATP depletion, and cell death (suicide hypothesis). In response to cellular damage by oxygen radicals or excitotoxicity, a rapid and strong activation of PARP-1 occurs in neurons. Excessive PARP-1 activation is implicated in a variety of insults, including cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-in-duced Parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The use of PARP inhibitors has, therefore, been proposed as a protective therapy in decreasing excitotoxic neuronal cell death, as well as ischemic and other tissue damage. Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma and subsequently in secondary damage of neighboring neurons hours after the insult. This secondary damage of initially surviving neurons accounts for most of the volume of the infarcted area and the loss of brain function after a stroke. One major component of secondary neuronal damage is the migration of macrophages and microglial cells toward the sites of injury, where they pro-duce large quantities of toxic cytokines and oxygen radicals. Recent evidence indicates that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may, therefore, be a promising strategy in protecting neurons from this secondary damage, as well. Studies demonstrating an important role for PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs is discussed with relation to nuclear factor kappaB and p53.

Abstract 13

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Based on the results from in vitro and in vivo studies and ongoing clinical trials, it is proposed to test the combination of a small mole-cule with PARP inhibitory activity (BSI-201, Iniparib) concomitantly with radiotherapy in patients who present with multiple non operable brain metastases. As radiotherapy is a local treatment targeting only the tumor, and because the molecule BSI-201 has shown no major toxi-city against tissues without DNA lesions and maybe a neuron protection after oxidative aggression, the proposed combination is expected to provide tumor-selective therapy and leading to a clinical benefit improvement.

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Place of TKI in the management of brain metastases of lung cancer

Antoine F. CarpentierAssistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Neurologieand Université Paris 13, UFR de Santé, Médecine et Biologie Humaine, Bobigny, France

Brain metastases are an important challenge in non small cell lung carcinoma (NSCLC), occurring in more than one third of the patients. Approximately 15% of the NSCLC patients have brain metastases at time of diagnosis (Sanchez de Cos et al., 2009). Whole brain radiotherapy (WBRT) is the standard of care for non resectable NSCLC brain metastases. Objective response rate after WBRT is around 30%, with a median survival of around 5 months (Metha et al, 2003; Stea et al., 2006). Tyrosine kinase inhibitors (TKI), like Gefitinib or Erlotinib, are becoming a standard of care in lung cancer patients having an activating mutation of EGFR. Extra-cranial response rate to TKI is around 10-20% (Herbst et al., 2003), with a much higher rate, around 70-80%, in EGFR mutated patients. TKI efficacy has also been demonstrated for brain metastases by several retrospective studies, with response rates ranging from 10 to 70 % in patients with unknown EGFR status (Ceresoli et al., 2004 ; Hotta et al., 2004 ; Chui et al., 2005 ; Shimato et al, 2006; Kim et al., 2009). In these studies, an excellent correlation between the systemic and the cerebral response rate to TKI was observed. We can therefore assume that the response rate of brain metastases to TKI alone in EGFR mutated patients is close to 70%. This high response rate of brain metastases to TKI challenges the usefulness of upfront WBRT. Indeed, postponing WBRT until time of cerebral progression could be a valuable therapeutic option. Alternatively, concomitant WBRT and TKI might be of particular interest. Precli-nical studies have shown that a synergistic effect was obtained when cancer cells were treated with ionizing radiation and Gefitinib (Baumann et al., 2007, Zhuang et al., 2009). A prospective Asiatic phase 2 trial using WBRT and Gefitinib reported a 81% brain response rate, a median PFS of 10 months, a median survival of 13 months and a good safety profile (Ma et al., 2009). Similarly, a phase one combining WBRT and Erlotinib showed an acceptable neurological safety profile at the 100 mg/day dosage (Lind et al., 2009). In a retrospective study of 18 patients treated with concomitant WBRT and TKI, the overall survival was of 22 months and the response rate was 85% in EGFR mutated patients (Gow et al., 2008). To address the respective timing of TKI and WBRT in RGFR-mutated patients, a randomized phase 2 trial (ARPEGE) is going in France. In this trial, half of the patients are treated with gefitinib alone, and the other half with concomitant WBRT and gefitinib, followed by gefitinib as a maintenance therapy.

Reference List 1. Baumann M, Krause M, Dikomey E, et al. EGFR-targeted anticancer drugs in radiotherapy: Preclinical evaluation of mechanisms. Radiother Oncol 2007;83:238–248. 2. Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E.Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004; 15(7):1042-73. Chiu CH, Tsai CM, Chen YM, Chiang SC, Liou JL, Perng RP. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. Lung Cancer. 2005 Jan;47(1):129-38. 4. Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, Carlini P, Boni C, Di Sarra S. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, non-small cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999 Apr 1;85(7):1599-605.

Abstract 14

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5. Gow CH, Chang YL, Hsu YC, Tsai MF, Wu CT, Yu CJ, Yang CH, Lee YC, Yang PC, Shih JY. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Ann Oncol. 2009 Apr;20(4):696-702.6. Herbst RS, Bunn PA Jr. Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res. 2003 Dec 1;9(16 Pt 1):5813-24.7. Hotta K, Kiura K, Ueoka H, Tabata M, Fujiwara K, Kozuki T, Okada T, Hisamoto A, Tanimoto M. Effect of gefitinib (‘Iressa®’, ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. Lung Cancer. 2004; 46(2):255-61.8. Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, Lee JS. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer. 2009 Sep;65(3):351-4.9. Lind JS, Postmus PE, Heideman DA, Thunnissen EB, Bekers O, Smit EF. Dramatic response to low-dose erlotinib of epidermal growth factor receptor mutation-po-sitive recurrent non-small cell lung cancer after severe cutaneous toxicity. J Thorac Oncol. 2009 Dec;4(12):1585-6.10. Ma S, Xu Y, Deng Q, Yu X. Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer. 2009 Aug;65(2):198-203.11. Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003 ; 21 : 2529 –36.12. Sanchez de Cos J, Gonzalez MAS, Montero MV, Montero MV, Pérez Calvo MC, Vinte MJ et al. Non small cell lung cancer and silent brain metastasis survival and prognostic factors. Lung cancer 2009 ; 63 : 140-145. 13. Shimato S, Mitsudomi T, Kosaka T, et al. EGFR mutations in patients with brain metastases from lung cancer: Association with the efficacy of gefitinib. Neuro Oncol 2006;8:137–144. 14. Stea B, Suh JH, Boyd AP, Cagnoni PJ, Shaw E; REACH Study Group. Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival. Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1023-30.15. Zhuang HQ, Sun J, Yuan ZY, Wang J, Zhao LJ, Wang P, Ren XB, Wang CL. Radiosensitizing effects of gefitinib at different administration times in vitro. Cancer Sci. 2009 Aug;100(8):1520-5.

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Leptomeningeal metastasis of breast cancer: diagnosis and treatment

Emilie Le Rhun 1, 2, 3

1 - CHRU de Lille : Pôle de Neurosciences et appareil locomoteur, Services de Neurochirurgie B et de Neurologie A, Hôpital R Salengro, Rue Emile Laine, 59 037 Lille cedex, France2 - Centre Oscar Lambret de Lille : Département de sénologie, Neurologie, 3 rue Frédéric Combemale, 59 020 Lille cedex, France3 - CH Valenciennes : Pôle 11, Service de Neurologie, Avenue Desandrouin, 59 300 Valenciennes, France

Around 5% of patients with breast cancer will develop leptomeningeal metastasis (LM). Due to its incidence, breast cancer is the main cause of LM. LM results in high morbidity and short overall survival despite treatment. The median survival of untreated patients with LM is 4–6 weeks and death often occurs due to progressive neurological dysfunction. Fixed neurological defects rarely improve with treatment, but progression of neurological deterioration may be halted in some patients and median survival can be increased to 4–8 months in breast cancer patients. An early diagnosis is needed in order to improve or stabilize the neurological status, maintain neurological quality of life and prolong survival. LM presents with pleomorphic clinical manifestations. Useful tests to establish diagnosis (MRI of the brain and spine, cerebrospinal fluid study) are not a part of usual assessments during metastatic breast cancer. Treatment requires a combination of intra-CSF and systemic chemotherapy despite proof of its benefit has not been established in randomized trials. Radiotherapy is used in the treatment of LM for palliation of symptoms, to decrease bulky disease and to correct CSF flow abnormalities. The aim of this presentation is to provide an actualized overview of (1) the useful tests to establish the diagnosis of LM, and (2) the different options of treatment.

Keywords Breast cancer, leptomeningeal metastasis, intrathecal treatment

Abstract 15

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