INTERNATIONAL BRAIN TUMOUR ALLIANCE (IBTA) www.theibta.org

Report of the

Trends in Central Nervous System Malignancies

Conference 2009

Budapest, Hungary

The IBTA booth at Budapest

Dr Bart Neyns Universitair Ziekenhuis Brussel, Brussels, Belgium. Dr Anne Rogiers, Brussels, Kathy Oliver (IBTA)

Kathy Oliver (IBTA). Dr Elizabeth B. Claus (USA)

Over 700 delegates in Budapest

Even before the first speaker rose to the podium you could spot one of the promising directions at the recent “Trends in Central Nervous System Malignancies” conference held in Hungary on March 27th and 28th.

The ballroom at the Intercontinental Hotel in Budapest stretched across a vast expanse where row after row of chairs had been placed in front of three giant screens.  In the chairs sat hundreds of delegates.

Whereas four or five years ago, attendance at a European CNS conference would have attracted a much smaller audience, over 700 clinicians, researchers, scientists, specialist nurses and allied healthcare professionals  converged on this Eastern European city to learn about the latest developments in brain tumour treatments.  This “full-house” trend - where a packed audience gathers to learn about the latest in brain tumour diagnosis and treatment - is indicative of the new and burgeoning focus of attention which, at long last, this devastating illness is beginning to experience.

Indeed, in his Welcome and Introduction, Professor Martin J van den Bent (Erasmus University Medical Center, Rotterdam, The Netherlands) - who was conference Co-Chair along with Dr Robin Grant (Western General Hospital, University of Edinburgh, UK) - said: “It’s good to see so many people in the audience. Very good.  It means we are treating the patients better.”

From the perspective of the brain tumour patient, family and caregiver community these are extremely welcome words.  For far too long, brain tumours have remained in the shadows on the cancer map. It is tremendously encouraging from our point of view to see so many professionals taking such a determined role and dedicated interest in discovering better treatment modalities for an illness which combines the very worst characteristics of neurological illnesses with the very worst characteristics of cancer and therefore causes such enormous heartache and devastation. 

A room brimming with so many specialists – as was the case in Budapest – gives the patient and caregiver community renewed hope that they are not alone and that there are steadfast efforts being made to improve survival and quality of life in what has notoriously been such a cruel and intransigent disease with very little in the way of effective treatments.

Background to the conference

The Budapest conference was also distinguished by its organisation. The EORTC (European Organisation for Research and Treatment of Cancer) and EANO (European Association of Neuro-Oncology) combined forces and produced an all-academia-organised conference.

The EORTC focuses on developing, conducting, coordinating and stimulating translational and clinical cancer research in Europe. Its goal is to improve the management of cancer and related problems by increasing survival and also patient quality of life. It encourages and facilitates multidisciplinary, multinational efforts between basic scientists and clinicians in the fight against cancer.

The EORTC Brain Tumour Group - whose outgoing Chair is Professor van den Bent and whose incoming chair is Professor Wolfgang Wick (Heidelberg University, Germany) - carries out the EORTC mission in the field of brain tumours by conducting phase I, II and III clinical trials in primary brain tumours and metastases.  This is achieved through an international, multidisciplinary group of neurosurgeons, neurologists, medical oncologists, radiation oncologists and basic scientists.

EANO is the pan-European organisation that represents all the medical and scientific disciplines involved in the diagnosis and treatment of tumours of the  central nervous system.  EANO congresses provide an opportunity for its numerous specialist members to update the brain tumour community on its work.  Forthcoming congresses include the 9^th EANO congress in Maastricht (The Netherlands) in September 2010 and the 10^th EANO congress in Marseille (France) in September 2012.

The Secretariat role for the Budapest meeting was managed by the conference unit of ECCO (the European CanCer Organisation), another key player in the European cancer arena.  ECCO is an umbrella organisation which exists to ensure that all European cancer patients access the best possible treatment and care.  ECCO also facilitates and promotes interaction between organisations involved in cancer research, education, treatment and care at the European level. 

It also organises congresses relevant to the cancer field.  Additionally, ECCO has a Patient Advisory Committee (PAC) which is comprised of representatives of a cross section of cancer patient groups and which helps inform ECCO regarding the patient and caregiver viewpoint on various issues.

With such a triumvirate (EORTC/EANO/ECCO) of high-level organisations involved, the “Trends in Central Nervous System Malignancies” meeting promised, as the programme notes said, a “rigorous review of the rapidly changing landscape of neuro-oncology”.

This was delivered during the two days’ worth of plenary sessions in Budapest which covered basic development in glioma; diagnosis and prognosis; supportive care; low grade gliomas; novel clinical trials; controversies in neuro-oncology; recent advances in surgery; and high grade gliomas.

The conference content

Denis Strangman (IBTA Chair) and Kathy Oliver (IBTA Co-Director) both attended the Budapest conference where the International Brain Tumour Alliance also had an exhibition booth.

Our first overall impression of the conference was that things are changing much faster in the world of brain tumours than ever before, although of course, they cannot change fast enough when someone you love is stricken with this cruel disease.  Patients and caregivers, who struggle on a day-to-day basis with this traumatic and vicious journey, want to see substantial progress made yesterday because we fear we will have no tomorrow.

Our second impression was that it seems to us that never before has it been so vital for multi-disciplinary teams to work together as this new era of combined therapies and treatment modalities becomes more refined and more demanding of cooperation between the various treatment arms of neurosurgery, radiation oncology and neuro-oncology.  The lines of demarcation between these three areas have certainly broken down, which is encouraging. 

For example, the importance of the neurosurgeon and the pathologist working closely together to ensure sufficient tissue samples are obtained and optimally preserved is crucial so that full analysis by the pathologist is possible. The oncologist will then require that analysis without delay so that all available options for relevant therapies can be explored.  With the further development of combination therapies and the enhancement of the effect of radiotherapy and temozolomide by the addition of further agents, the radiation oncologist is also becoming more fully involved with the extended care of the patient.

The third point which struck us – and continues to do so at each of the many brain tumour conferences the IBTA attends – is that, as more and more answers are found to the many complex issues surrounding brain tumours and their treatment, so there are even more new questions arising.

It was many of these new questions, discussed at the Budapest conference, which provided insights into some of the brave, new, and hopeful directions in which brain tumour treatment is heading.

Below are some of the highlights of this meeting, as seen from the brain tumour patient and caregiver viewpoint. 

Full Speaker Abstracts can be accessed here:

http://www.ecco-org.eu/binarydata.aspx?type=doc/0080003_ProgrammeBook_Speaker_Abstracts.pdf

Poster Abstracts can be accessed here:

http://www.ecco-org.eu/binarydata.aspx?type=doc/0080003_ProgrammeBook_Poster_Viewing_&_Abstracts_33_63.pdf

Supporting Handouts to Presentations can be accessed here:

http://www.ecco-org.eu/binarydata.aspx?type=doc/WEB_Handouts.pdf

Session I – Basic Developments in Glioma

This opening session of the Budapest conference covered basic developments in glioma and the first presentation was given by Dr F Lang (University of Texas MD Anderson Cancer Center, Houston, Texas, USA) on the “Role of mesenchymal stem cells in the biology of gliomas”.

Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types. The researchers cultured fresh surgical specimens of human gliomas. One of their findings was that these tumour-derived hMSCs (TD-hMSCs) were more commonly isolated from high grade (96% of specimens) compared with low grade gliomas (29% of specimens) "suggesting that TD-hMSCs are involved in tumour progression".

This was followed by a talk on “Integrins: function and role in cancer” from Professor W Wick (Heidelberg University, Heidelberg, Germany) Integrins are critical for glioblastoma multiforme physiology, affecting migration of cells, angiogenesis and proliferation.  The new therapy Cilengitide inhibits integrins. Professor Wick noted that dosing may be an issue in this therapy and that efforts are being made to identify the appropriate dose.

The final presentation in Session I was given by Dr G Reifenberger (Heinrich-Heine University, Dusseldorf, Germany) on “Molecular lesions in oligodendrogliomas”.  Discussing loss of chromosomes 1p and 19q, MGMT, the IDH1 gene and other chromosomal gains and losses, Dr Reifenberger’s presentation concluded that “Some of the molecular alterations detected in oligodendroglial tumours, in particular the 1p/19q deletion status, have already gained clinical relevance with respect to the prediction of prognosis and the stratification of patients in ongoing clinical trials.  Nevertheless, it has to be emphasised that not only 1p/19q deletion and MGMT promoter methylation, but yet other of the complex molecular aberrations in these tumours, may also influence treatment response and patient outcome.”

Session II – Diagnosis and Prognosis

Professor M Weller (University Hospital, Zurich, Switzerland) delivered a presentation which addressed one of those “new” questions we mention above as having arisen in response to new answers.  “In today’s clinical practice, does it have any value to assess MGMT promoter gene in gliomas?”

There was research during 1996-98 on MGMT, albeit under another name. Today cost is an issue but the test will cost less later on.  In Germany and Switzerland it is not common to see patients who have not already received temozolomide. In Germany they do not extend TMZ beyond six months. When they request an MGMT test in the everyday clinical setting, Professor Weller said he asks patients why they want to have this test, and when he describes the still-existing questions surrounding MGMT testing and MGMT data, fewer proceed with the test.

Professor Weller concluded that, at the present time, although determining MGMT status is important for clinical trial work, “The MGMT status determined by MSP [methylation-specific polymerase chain reaction – MS-PCR, MSP] or by any other method should not be used to make treatment decisions outside clinical trials.”  The use of MGMT assessment outside of clinical trials, he explained, needs further validation.  Current assays vary and are complicated and even the experts do not yet agree which technique is best.

Professor R Stupp (University Hospital CHUV, Lausanne, Switzerland) began this session with an overview on the future for personalised therapy for glioma. The hunt for molecular profiling signatures is on and new ones need to be found and brought into clinical routine.  There is a need for reliable and reproducible testing, standardised assays and further validation.  Most importantly, said Professor Stupp, the availability of tissue blocks is crucial because “tissue is the issue!”. In order to progress personalised therapy for glioma, for which there most definitely is a future, it is vital to obtain optimally preserved tissue blocks which can be analysed and tested. “We need fresh frozen tissue, and/or paraffin embedded (samples)”.

Professor Stupp commented that in regard to MGMT testing “Only do it when it has a clinical consequence. The patient is depressed; there is no need to have the doctor depressed as well”. We have patients in front of us, not [just] tumours”. He also added that its use results in little utility if there is no adequate alternative strategy available. 

Dr K Herholz (University of Manchester, UK) spoke on “The role of PET [Positron emission tomography] in the management of glioma” and was pleased that the subject of PET had for once been included in a plenary session. He said the main issues as far as brain tumours are concerned are that PET is relevant in the transition from a Grade 2 to a Grade 3 tumour, and in monitoring the therapy for a Grade 4 tumour, but PET is only one component; others are vascular and cellular changes in the tumour. He mentioned in passing that PET had been very relevant in regard to lymphoma.

 He said that labelled amino acids provide better contrast to normal brain than FDG, which is commonly used in PET scans. They show increased uptake, even in low grade gliomas in the absence of contrast enhancement on MRI and provide information on the extent of infiltration in malignant gliomas.

Session III – Supportive care

Two very important presentations – one on cognitive rehabilitation for glioma patients and the other on end of life treatment decisions were given by K Gehring (Tilburg University, Tilburg, The Netherlands) and Dr A Pace (Regina Elena National Cancer Institute, Rome, Italy).

Ms Gehring posed the question: “Is cognitive rehabilitation in glioma patients effective?”  In answer, she explained her institution’s “multifaceted cognitive rehabilitation programme on cognitive functioning, fatigue and quality of life in glioma patients whose disease was in remission” and a randomised controlled study.  Concluding that this trial provided initial evidence of an effective treatment for cognitive deficits in glioma patients, Ms Gehring called for further investigations to be carried out. She cast doubt on existing studies of cognitive deficits in glioma patients because of their methodological inadequacies.

Dr Pace spoke of the hugely complex needs of malignant brain tumour patients in the advanced stages of the disease.  He described a palliative home-care pilot which his institution, the Regina Elena National Cancer Institute in Rome, had initiated which was supported by the Regional Health System. Dr Pace described how “The aims of this model of assistance are to meet patients’ need of care during the evolution of the disease, to provide rehabilitation at home, to improve patient’s quality of life with palliative care and to facilitate death at home.”  He provided statistics about the most frequent symptoms experienced in the last four weeks of life of those who died at home. For brain tumour patients end of life decisions concern mainly “no-treatment” decisions. He noted that “The large majority of patients with brain tumours die with a process that has been defined as ‘peaceful death’, with progressive neurological deterioration”. Dr Pace volunteered that only a little over 50% of brain tumour patients are aware about their prognosis. He called for more education and awareness in palliative care and end of life strategies and suggested that new models of care should be developed to meet the needs of this very challenging group of patients. 

Session IV – Low Grade Gliomas

The treatment of low grade gliomas is extremely controversial, ranging from the “watch and wait” approach to a much more active treatment regimen and combinations in-between.  The indolent nature and variable behaviour of these tumours makes a one-size-fits-all approach impossible.

In his presentation on “Integrating MR imaging in decision-making, when to stop ‘wait and see’ in low grades?” Dr J Rees (Institute of Neurology, UCL National Hospital for Neurology and Neurosurgery, London, UK), explained how unpredictable the timing of malignant transformation is from patient to patient.  In his institution, a six year prospective multimodality MR study of untreated low grade glioma was carried out, looking at markers of early malignant transformation (EMT) using MRI evaluation and determining that: “Integrating volume and perfusion parameters into the overall evaluation of LGG behaviour has been shown to be feasible and should be integrated into the standard MRI evaluation as they offer a more tailored approach to the detection of EMT.”

Dr M Klein (VU University Medical Center, Amsterdam, The Netherlands) spoke on “Should cognitive measurements be part of standard care for low grade glioma patients?” Dr Klein pointed out that a better understanding of the natural history of low grade gliomas has led to an interest in earlier treatment, as opposed to the “wait and see” or “wait and scan” policy. With increased survival there has been a focus on cognitive functioning and health related quality of life but their evaluation can be time consuming and self-evaluation by the patient of their functioning might be problematic. He called for more sensitive measures in future trials.

Session V – Novel Clinical Trials

Three different therapy approaches were discussed at this session, the speakers for which included Professor R Stupp (mentioned previously), Dr O Chinot (CHU de la Timone, Marseille, France) and Dr D Bigner (Duke University Medical Centre, Durham, North Carolina, USA).

Professor Stupp gave an update on cilengitide (an integrin inhibitor - integrins activate signalling pathways, regulate cell adhesion, proliferation, survival and migration). Professor Stupp explained that in the Phase II trial for cilengitide, “Compared to our historical control overall survival was promising, notably in the patients with a methylated MGMT gene promoter. We hypothesize that cilengitide normalizes tumor vasculature and allows for improved perfusion with the chemotherapy agent. In addition, cilengitide has a direct antitumor effect as well as it inhibits tumor cell migration, a major cause of recurrence of the disease outside the initial treatment field.”  In the recently launched Phase III randomised trial involving the manufacturer and the EORTC, patients will be first tested for their MGMT status before proceeding further with this trial. 

Professor Stupp again emphasised the crucial requirement for the availability of tumour tissue in studies of cilengitide (and indeed any ongoing or planned trials for glioma).

Dr Chinot spoke about bevacizumab (an anti-angiogenesis therapy) in newly diagnosed glioblastoma patients, providing a review of previous clinical trials.  He described the new Phase III Roche-conducted international trial for bevacizumab (Avastin).  This is study BO21990, which is a randomized, placebo-controlled trial of bevacizumab in combination with radiotherapy and temozolomide for newly diagnosed GBM in which 920 eligible patients will participate.  This is a two-armed study, one with patients receiving radiotherapy + temozolomide and the other with patients receiving radiotherapy + temozolomide + bevacizumab. 

Dr Bigner’s presentation, entitled “Immunotherapy Against EGFR vIII: Ready to Enter Randomized Studies?” provided an overview of immunotherapy clinical trials including the DC Victori trial, the ACTIVATE trial, ACTII trial, ZAPIT trial, ACTIII trial.  The detailed slides for this presentation can be found on page 43 at the above-mentioned web address for “Supporting Handouts to Presentations”.

Session VI – Controversies in Neuro Oncology

Three topics made up this fascinating and provocative session at the Budapest conference.

(1) Should pediatric gliomas be treated like adult gliomas?

(2) Brain tumour patients must be legally treated by multidisciplinary teams

(3) Diagnosis of grade III tumours: do molecular markers increase diagnostic uncertainty?

The first presentation by Dr J Grill (Gustave Roussy Institute, Villejuif, France) highlighted the fact that drug development for pediatric brain tumours is a key issue and that the selection of drugs to test is currently decided based on data for adult brain tumour patients.  This provides a number of challenges which lead him and his colleagues to conclude that pediatric gliomas need their own focus of attention based on biologic data from these brain tumours specifically but there could be merit in undertaking parallel trials involving adults and children.

He pointed out that in children three-quarters of gliomas are low grade, whereas in adults three-quarters are high grade. The location is also different with 50% of paediatric brain tumours in the brain stem. In France 24% have been GBMs and 24% oligodendrogliomas. He observed that there had been low efficacy for temozolomide in paediatric patients and questioned whether there might be too much MGMT activity in these tumours. He also noted that rarely does one see a transformation in children from a low grade to a high grade.

Dr D Levy (University of Sheffield, Sheffield, UK) spoke about the benefits of a multi-disciplinary team (“MDT”) approach to treating brain tumours so that patients can receive the highest standard of care via a holistic and coordinated approach which involves neurosurgeons, oncologists, neurologists, neuropathologists, neuroradiologists, specialist nurses and allied healthcare professionals. 

He noted that in the UK brain tumours were the second most common cause of cancer death in the 18-40 years age group.

As a patient organisation, we wholeheartedly support the MDT approach although we recognise that unfortunately in some countries, where specialists are not congregated around centres of excellence, or there may not even be centres of excellence, that this might be a difficult goal to achieve. However, perhaps this particular challenge can be addressed via greater use of teleconferencing and video-conferencing so that more and more brain tumour patients, regardless of where they live, can benefit from improved coordination of services and a gold-standard level of appropriate care from a multi-disciplinary team.  As we mentioned in our introduction above, with the advent of combination therapies to treat brain tumours, never has it been more important to take a multi-disciplinary approach to treating this horrific disease. We have uploaded a synopsis of Dr Levy’s presentation to our website which may be accessed via the April E-News. Dr Levy also mentioned that he had a neurosurgical colleague who gave his mobile number to patients and in one year only one patient contacted him.  This possibly reflected the ‘nice’ nature of brain tumour patients – they do not wish to be an inconvenience.

Professor M J van den Bent presented on “Diagnosis of grade III tumours: do molecular markers increase diagnostic uncertainty?” Molecular markers are playing an increasingly important role in the treatment of brain tumours.  Professor van den Bent highlighted pathology reviews in which inter-observer variation and lack of consensus occurred, emphasising the need to critically evaluate and standardise approaches to molecular analyses.  Further, he stated that, although it is a very important prognostic factor, “still not enough is known about the role of MGMT to use it in everyday clinical decision-making”. He made the distinction between a marker that might be relevant for prognosis, but not necessarily for treatment decisions. He suggested that the IDH1 mutation may have prognostic significance but this needs to be confirmed.

Session VII – Recent Advances in Surgery

Dr C Dirven (Vrije Universiteit Medical Centre, Amsterdam, The Netherlands) and Dr W. Stummer (University of Dusseldorf, Dusseldorf, Germany) both presented in this section with Dr Dirven providing a review of “New techniques in Surgery” and Dr Stummer addressing the question: “Do the benefits of extensive resection outweigh the risks?” Summarizing the risk of possible serious adverse events resulting from extended resections and balancing this against the benefits, Dr Stummer compared navigation in malignant glioma surgery to a journey past the mythical Greek creatures of Scylla and Charybdis.  As myth recounts, situated on opposite sides of the Italian Strait of Messina, Scylla (here symbolically representing brain function) and Charybdis (symbolically representing residual tumour), were just close enough to each other so that both could present a critical danger to passing sailors (here symbolic of the neurosurgeon’s role).  So it is important to steer some kind of middle path, not getting too close to Scylla (and thus damaging brain function) but getting close enough to Charybdis (residual disease) to remove as much tumour as possible.

Dr Dirven noted that an intraoperative MRI facility for neurosurgery could cost Euros 5m and a new method involved using the facility for a component of the operation and then moving it out of the operating theatre for use elsewhere.

Session VIII – High Grade Gliomas

Three very interesting presentations rounded off the Budapest meeting.

Professor M Brada (The Institute of Cancer Research, Royal Marsden NHS Trust, Sutton, UK) presented the results of “A randomised trial of procarbazine, CCNU and vincristine (PCV) vs temozolomide (5-day or 21-day schedule) for recurrent high grade glioma (MRC BR12, ISRCTN83176944).”   This trial represented the first time that temozolomide for recurrent high grade glioma was directly compared with PCV chemotherapy.  He acknowledged that “some of you may think that such a comparison was well past its sell-by date”.  The trial had been designed during 2000-2001, accrual took place between July 2003 and January 2008 in 36 centres. But he added that there were some surprising and noteworthy results. The presentation abstract concluded that “While TMZ did not show a clear benefit compared to PCV in patients with recurrent HGG, the comparison of the two TMZ schedules demonstrated that the apparently more intensive TMZ-21 regimen was inferior to TMZ-5. This challenges the current understanding of increasing TMZ dose intensity by prolonged scheduling.”

Professor W Wick (Heidelberg University, Heidelberg, Germany) addressed the conference on “An update on the NOA4 trial: what are the new questions?” The NOA4 study was a Phase III, multicentre, open-label trial designed in the late 1990s which compared the efficacy and safety of radiotherapy versus chemotherapy (PCV or temozolomide) for newly diagnosed grade 3 anaplastic astrocytoma patients, median age 45 years.  A translational study looked at the clinical significance of 1p/19q chromosome deletion and also MGMT in these tumours.  Interestingly, the study found that MGMT promoter methylation was associated with prolonged progression-free survival in the radiotherapy arm of the trial.

Professor M Westphal (University Hospital, Hamburg, Germany) reported on “Sitimagene ceradenovec (Cerepro ®) gene therapy and ganciclovir for newly diagnosed high-grade glioma: current status of the randomized phase III trial”.  An international trial for this therapy approach took place in Europe and Israel and involved 250 patients with operable high grade glioma in 38 centres. The trial ran from November 2005 to April 2007.  Results, reported Dr Westphal, are encouraging.  Safety analyses showed that “the treatment was safe and had no unexpected safety profile” and “the first analysis of efficacy data which is still in need of further maturation showed a statistically significant treatment effect.”  He noted that it may be the first trial that shows that gene therapy works in a human. 

Conclusion

Dr R Grant (Western General Hospital, University of Edinburgh, UK), on behalf of EANO, brought the meeting to a close following the announcement of next year’s EANO conference from September 16 – 19 in Maastricht, The Netherlands.  The next joint EORTC/EANO “Trends in Central Nervous System Malignancies” will take place in Bucharest, Romania from March 25 – 26, 2011.

The international brain tumour community watches the development of all therapies discussed at conferences such as these with great interest, anticipation and hope that they bring a rapid, meaningful and sustained improvement in brain tumour treatment to the hundreds of thousands of people of all ages around the world whose lives have been touched by this unrelenting and brutal disease.

Ref: Budapest Conference 2009 Report FINVER 28Apr09 1857

NOTE: This collection of laymen’s personal observations made during presentations at the March 2009 “Trends in Central Nervous System Malignancies” conference in Budapest, Hungary, is based on notes taken during the various sessions.  Readers are advised to verify the information and consult original published source material.  The comments in these notes are not in any way meant to constitute medical or other advice or recommendations.  These notes have been compiled in good faith.  They are in no way intended to be a complete record of what took place and are based on personal notes taken without the backup of any recordings of speakers.  No verification (research or otherwise) of matters included in these notes has been undertaken by or on behalf of the authors.  The authors do not accept responsibility for any inaccuracies or misinformation, errors or omissions in or arising from these notes.  Regardless of information appearing in notes such as these, medical professionals should always be consulted before any decision is made regarding treatment or any course of treatment is undertaken.