Press release

ARCHADEEuropean Hadrontherapy Research Centre,in Caen, Normandy

A project of general interest:to advance hadrontherapy research to develop cancer treatment

Faced with increasing numbers of cancer cases, a major public health issue, researchersand practitioners are mobilising the world over. This pathology is rising sharply in Europe:between 2000 and 2020 the number of new cases is expected to rise by 50%. Hence inFrance, cancer, which in the last few years has been the biggest cause of death, involvesover 350,000 people each year (INVS forecast for 2010). Patients receive surgery,chemotherapy and radiotherapy treatments, and often a combination of these.

Since the 1990s, proton hadrontherapy (or protontherapy) is another therapeutic weaponin the fight against cancer. This new high precision form of radiotherapy with protonbeams is growing fast in the USA, Europe, Japan and China. It is expected that some 10 to15% of cancers that come in for conventional radiotherapy will eventually be treated withprotons, which for some cancers are more precise than X-rays. Owing to the limitednumber of clinics open around the world, only a small proportion of cancers requiringradiotherapy can currently receive proton treatment. So hadrontherapy has high growthpotential in order to better adapt the available treatment to people’s medical needs.

A more recent development, hadrontherapy with carbon ion beams brings fresh hope.At the three carbon ion hadrontherapy centres currently operating in Japan and inGermany, the results look very promising, notably for certain cancers that are resistant toconventional treatments. Extremely precise, like protons, but more effective againstcertain tumours, this therapy opens up new prospects for patients suffering from chemo-and radioresistant or inoperable cancers.

For the medical community, the innovative character and the fast growth of carbon ionhadrontherapy lead to substantial research requirements. We now need to compare itwith other forms of treatment, to understand which tumours and which patients reallyneed this treatment, to develop tools and knowhow, to make better use of this newweapon and further improve their chances of a cure.

The ARCHADE European Hadrontherapy Research Centre has been set up with this inmind. It is to be the first centre in the world exclusively dedicated to hadrontherapyresearch.

Press release

Since its origin, the ARCHADE project has been pursuing three goals:- accelerate fundamental and applied hadrontherapy research, especially with

regard to the use of carbon ions,- develop clinical research and demonstrate the therapeutic value of this new

weapon as compared with conventional treatments,- contribute actively towards wide dissemination of hadrontherapy across the

globe.

ARCHADE will have a beam dedicated, first, to research into biology and physics, andsecondly, to clinical research. Every effort will be made to develop the researchprotocols and define the treatments of tomorrow.

By the end of 2015, patients will be treated in Caen within the framework of researchprotocols. The results will be compared with conventional radiotherapy and someinvaluable feedback will become available in the years that follow.

ARCHADE also stands at a watershed in the technological development ofhadrontherapy. The cyclotron for therapeutic purposes developed by ARCHADEforeshadows the second generation of compact machines that ought to be available verysoon to the entire medical community and to cancer patients worldwide.

The cyclotron, designed by the world leader IBA (Ion Beam Applications), capable ofdelivering carbon protons and ions, will be a world first.

This accelerator is designed to be more compact, easier and much cheaper to operate, anda smaller investment than existing hadrontherapy machines. ARCHADE’s core research willinvolve the use of carbon ions to treat cancerous tumours.

These are decisive advantages which ought to facilitate implementation and disseminationof these innovative methods of treatment on a massive scale. This will help to developnew centres in France and throughout the world in order to fight cancer moreeffectively.

Finally, ARCHADE, a cluster of health-research activities located in Caen, is, astructuring project for Normandy Region, in terms of both research and industrialdevelopment. It will generate technology transfers and significant economic benefits forthe area, including new jobs.

Press contact:Claire MontémontPress agent for the Archade projectclaire.montemont@wanadoo.frTel: 02 31 29 16 96 – mobile: 06 10 15 04 18

Website: www.archade.fr

Gathering researchers around ARCHADE

ARCHADE, a collaborative research and development project with nationwide andEuropewide scope gathers a large number of people and institutions. Various levels ofcooperation are being organised to take ARCHADE further.

At national level, ARCHADE is part of a nationwide dynamic, notably in the context of afour-party agreement with existing protontherapy centres at Orsay (Institut Curie), theAntoine Lacassagne Centre in Nice and the Centre ETOILE in Lyons (a future clinicalhadrontherapy centre). This agreement sets out the strategic directions for each partnerand organises their cooperation under the impetus of INCa (Institut National du Cancer).

Also, a Scientific Interest Group (SIG) called ‘Research & Developments in Hadrontherapy’was set up at the end of 2009 by the National Scientific Research Centre (CNRS),‘CNRS/IN2P3” (GDR-CNRS MI2B, Modelling and Instrumentation for Biomedical Imaging),and the ARCHADE Association. Other partners like the CEA or ETOILE will be joining this SIGin the very near future.

A cooperative effort will be developed with the ARRONAX nuclear medicine researchcentre in Nantes and the various cancer treatment centres in the Grand Ouest region andthe Paris area (Ile-de-France).

The ARCHADE research centre will also make it possible to generate revenue byoffering beam time and training courses to the research centres, clinical centres andindustrialists of Europe. This collaborative platform will be largely open to theinternational scientific community.

Developing a structuring health-research cluster in Caen

To develop the cyclotron, ARCHADE is relying on the technology and science complexon the north side of Caen which has an overall skills set like nowhere else in Europe.

ARCHADE, currently a non-profit association (under the 1901 Act) includes the FrançoisBaclesse Centre (cancer treatment), the CHU (Caen University Hospital), the ENSICaenschool of engineering and the University of Caen-Basse Normandie; it is chaired byProfessor André Valdazo of the CHU in Caen.

The research project was worked out with the partners headed by Professor Jean Bourhis,head of the radiotherapy department of the Gustave Roussy Cancerology Institute(Villejuif, Paris area) and Chairman of the European Radiotherapy Society (ESTRO).

Around ARCHADE, Caen’s north Campus offers an outstanding scientific environmentwhich is particularly conducive to developing the project. The project’s initial phase(preparation of the physics and radiobiology tools and models prior to installing thecyclotron) will be relying on existing resources and facilities. The project’s second phasewill be to validate and optimise the new C400 cyclotron for medical purposes.

This combination of skills was a key element in deciding IBA to install its prototype atCaen to validate its use for treatment. ARCHADE helps to advance Caen’s north Campusas a recognised centre for health and research.

Raising an industrial sector in Normandy

The Archade project is a structuring project for Normandy. It will lead to thedeveloping of a whole industrial sector centred on the building of cyclotrons. Majoreconomic benefits for the area are expected.

IBA intends, to the fullest possible extent, to call upon local business, either in jointventures or as subcontractors, for manufacturing components for the prototype C400cyclotron for medical purposes.

Accelerators of the same type will go into series construction. With a unit value of severaltens of millions of euros, they will be sold to all parts of the world. This recurringproduction should provide steady business for the region’s enterprises in a sector withhigh added value and with high growth potential in global terms.

Moreover, the technology transfers resulting from the ARCHADE research will bring growthto local businesses and will boost new startups in areas such as physics, accelerators,dosimetry, precision mechanics, robotics, electronics, data processing, medical imageryetc.

Implementing ARCHADE: an innovative package from public and private sectorpartners

Normandy Region, which has backed the project from the origin, is the leader of thisjoint venture involving institutions, businesses and banks which together set upSAPHYN (SAnté et PHYsique Nucléaire – health and nuclear physics) in 2009.

This semi-public company will be developing an experimental R&D programme in the fieldof nuclear physics applications in the health sector. SAPHYN will be deploying innovativeradiotherapy, nuclear medicine and medical imagery projects. As part of the collaborationand research agreement with IBA, SAPHYN will be hiring a team of around tenresearchers to validate and optimise the cyclotron for medical purposes.

SAPHYN will also be acting as a development tool. It will encourage technology transferstowards businesses to upgrade their technological status, contributing to the growth oftheir business and more generally to employment in Normandy Region.

SAPHYN and IBA in 2010 set up the joint-venture CYCLHAD, a holding company to supplyinvestment (cyclotron, associated facilities and building). In 2011, more investors willalso be contributing to CYCLHAD which will become a hadrontherapy resource centre bylate 2015. CYCLHAD will be selling beam time to research centres and to clinical andindustrial centres in Europe.

ARCHADE fundingThe funding requirement for the Archade project is 100 million Euros:

- 80 million Euros to purchase the cyclotron and its facilities, and construction of thebuilding;

- 20 million Euros to cover design, operation and financing costs.

ARCHADE is financed with funding from public and private sources.As regards CYCLHAD, 16 million Euros of equity capital will be raised including 3 million contributedby SAPHYN, 3 million by IBA and 10 million by private investors.A loan from a banking syndicate will complete this funding with a further 84 million Euros. Otherresources will be sought in order to minimise the borrowed portion, with the appeal for Europefunding, to the National Research Agency and to sponsorship.

The ARCHADE timetable

October 2009: Creation of the semi-public company SAPHYN (SAnté et PHysique Nucléaire)March 2010: Creation of CYCLHAD (a CYCLotron for HADrontherapy), the future hadrontherapyresource centre.

September 2010: Signing of the collaboration and research agreement between SAPHYN and IBA;signing of the cyclotron purchase and maintenance agreement between CYCLHAD and IBA.

2011: Preparation of the research tools and models.

June 2012: Start of construction of the building intended to house the cyclotron and thehadrontherapy research centre on Caen’s north Campus.

December 2013: Completion of the building construction work.

January 2014: Assembly of the cyclotron and delivery of its equipment.

December 2015: the ARCHADE centre becomes operational, it develops biology and physics researchprogrammes and takes in the first patients as part of clinical research protocols.

Annex 1 – Hadrontherapy : high precision radiotherapy

Hadrontherapy, a more precise form of radiotherapy by a beam of particles called hadrons(protons and carbon ions), is used to target the tumour with great precision and depositthe required energy in it while minimising the impact on the surrounding healthy tissue.The beam is guided so as to target spot by spot different parts of the concerned tumourarea.

Some thirty facilities using protons are in operation around the world (around 66,000patients treated to date). Two protontherapy clinics are operational in France, the AntoineLacassagne Centre in Nice and the Curie Institute at Orsay.

Carbon ions, a major new development

A new step was taken ten years ago with the use of carbon ion beams. These representseveral advances in solving the problem of certain cancers’ resistance to conventionalradiotherapy.

Ballistic advantage: the dose of irradiation is as precise as with protons, at the tumour.

Biological advantage: carbon ions are much more effective on certain cancers that areinoperable or resistant to conventional X-rays. Depending on the type of tumour, thebiological efficacy of the dose delivered may be 1.5 to 3 times greater. The irradiationneeded to produce a similar level of destruction of tumour cells is therefore two or threetimes less intense than with protons or X-rays.

This extra biological efficacy and ballistic accuracy of carbon ions is a majorbreakthrough in the field of radiotherapy that is beginning to achieve worldwiderecognition. Feedback from clinics in Japan and Germany (6,000 patients treated to date)indicate its efficacy and the low level of side effects. It seems especially suitable fortreating certain kinds of tumours (brain tumours, salivary tumours, melanomas, sarcomas)or deep-seated tumours (inside the skull…).

Carbon ion hadrontherapy is a dynamic field worldwide with two centres opened inJapan and more being built, one centre opened in Germany and two more underconstruction, a centre opening in Italy, a centre in the pipeline in China…In France, ETOILE in Lyons will be dedicated chiefly to clinical practice.

ARCHADE in Caen will be world’s first centre devoted to hadrontherapy research todemonstrate its efficacy, and help researchers, clinicians and patients.

Annex 2 - The cyclotron, ARCHADE’s research tool

Hadrontherapy destroys cancerous tumours by depositing energy produced by radiation.Accelerated to sufficiently high speeds, the ions enter deep into the human body up toaround 30 centimetres/1 foot). These beams are generally produced by synchrotrons orcyclotrons.

ARCHADE has opted for a cyclotron capable of accelerating both carbon ions andprotons. This accelerator was designed by the Belgian company IBA, a world leader inmedical cyclotrons. It foreshadows a new generation of machines which will be cheap toaccess, thereby democratising their utilisation for the benefit of patients.

The IBA C400 cyclotron will be a world first.Apart from its carbon ions–protons versatility, it will be much more compact than asynchrotron, with a diameter of just 6 m by 4 m high (a carbon ion synchrotron measuresaround 25 m in diameter). This compactness is made possible by technological innovations,notably cryogenics, used to increase the magnetic field. The appliance’s smaller size willmoreover reduce the size of the building to house it.

This accelerator is a cheaper investment and also less costly to operate, as it requires 3times less thermal power and hence less electrical energy (700 kW compared with 2 MWfor a synchrotron).

Its technology is less complex than a synchrotron, making for greater reliability and easiermaintenance. It is estimated that the price of carbon ion treatment will be roughly thesame as for chemotherapy, although more expensive than conventional radiotherapy.

Lastly, another feature is the production of a continuous beam (constant electric andmagnetic fields), simplifying the sequencing of irradiations.

This cyclotron will then be constructed in series for use across the globe.

A partnership of excellence with IBA, the world leader in cyclotrons for medicalapplications

The IBA Group currently holds a 60% stake in the global market for protontherapycyclotrons; it has equipped 16 protontherapy centres across the world. IBA has alreadymade 200 cyclotrons for radiopharmaceuticals production and a few units for research, likethe ARRONAX C70 at Nantes.

The C400 cyclotron developed for ARCHADE is the outcome of in-depth work by IBA, inconjunction with the world famous specialists and experts of the JINR (Joint Institute ofNuclear Research, Dubna, Russia). The results were set out before a panel of internationalexperts: MIT (Massachussets Institute of Technology, USA), BNL (Berkeley NationalLaboratory, USA), AGOR (University of Gröningen, Netherlands), LNS (Laboratori Nazionalidel Sud, Catania, Italy), Orsay Nuclear Physics Institute, GANIL (Grand AccélérateurNational d’Ions Lourds, Caen).

Their conclusion fully validates the project’s technical feasibility. Its realisation, at a timewhen hadrontherapy is coming into its own, will also provide leverage for developingnew techniques for accelerators dedicated to therapy.

The cyclotron

In this circular machine the ions (protons, alpha particles or carbon) are injected into thecentre of an electromagnet fitted with coils cooled with liquid helium (superconductivity).

A set of electrodes accelerates them continuously inside the magnetic field of constantvalue. The frequency of the accelerator electric field is also constant. After the beam isejected out of the machine, the energy variation is done by slowing down the beam to agreater or lesser extent by interposing sheets of graphite of varying thicknesses. This smalldiameter beam is directed at the patient.

The beam energy is adjusted to reach the different layers of the tumour in succession.After fine-tuning the contours of the tumour by imaging, its representation in 3 dimensionsis virtually sliced into layers, each one being divided up into a checkerboard. Thenecessary dose of radiation is calculated for each square on the checkerboard.

The particle beam sweeps across the layer, stopping at each position until the planneddose has been deposited. The depth of beam penetration can be modulated to anythingbetween 20 and 300 mm.

The total time taken for an irradiation session will be about two minutes.

The building housing the European Hadrontherapy Research Centre

The 2,500 m2 building which is to house the cyclotron and the ARCHADE research anddevelopment centre will be centrally located on the science and technology cluster inCaen, on 7,000 m2 of land east of the GANIL location.

Schematic diagram

clinicalresearch

Biology and physicsresearch

energyselector

cyclotron

Annex 3 – ARCHADE research

The research requirements are substantial in order to develop and optimise utilisationof carbon ion beam hadrontherapy. While much research has highlighted its value, thedifficulty involved in accessing beam lines dedicated to research has limited the evaluationand characterisation of the biological impact of carbon ions. Similarly, very little work hasbeen done on the direct effects in vivo.

Many fields of investigation still need to be explored in biology, physics and clinicalresearch: why and under what circumstances are carbon ion beams more effective? Howdo we optimise their utilisation? How many sessions per patient? What type of patient andcancerous tumour will benefit from such treatment?

ARCHADE, the world’s first hadrontherapy research centre is opening in Caen toanswer these questions.Five lines of research have been defined.

Numerical simulation

This work will make it possible to calculate precisely the irradiation dose directed spot byspot at the tumour placed within the surrounding healthy tissue.

The ion beam interacts many times and in many different ways with the atoms of thetissue it passes through. Its nature and characteristics are themselves modified by theseinteractions, in such a way that forecasting the dose deposited along the way requiressome very complex calculations. These are done with the help of software programs usingthe physical data drawn from experimenting or from theoretical models.

The ARCHADE research will adapt the existing software programs, check their validity andintroduce methods to cut the calculation times for these simulations which are currentlyvery long.

Coordination: Dr Cussol (IN2P3/ENSICAEN).

Dosimetry and beam control

Optimisation of measurement of the irradiation dose and monitoring of the carbon ionbeam quality form the second line of the ARCHADE research.

Utilisation of an ion beam requires precise control of its geometry, its energy, its intensityand the dose delivered.

While the necessary instrumentation for protontherapy exists, this is not the case forcarbon therapy where further developments will be necessary. Particular attention will begiven to improving methods for instant measurement of the dose during treatment, a littleexplored area to date.

These measurements call for in-depth knowledge of the physical data relating to theinteractions between the beam and the tissue components; a programme of experimentswill be drawn up and carried out in order to collect these data.

Coordination: teams of Prof. Colin and Dr Fontbonne (ENSICaen), in conjunction withIN2P3 and CNRS.

Hadronbiology

The aim of the ARCHADE research is to better understand the biological parameters thatdetermine how tumours and healthy tissue respond to carbon ions.

Some particularly innovative research programmes will allow to compare different types ofradiation (X-rays, carbon protons and ions). This research is necessary in order to schedulecourses of treatment aimed at tumours that are usually resistant to conventional forms oftreatment.

Coordination: Dr Lefaix (LARIA/CEA).

Planning of the carbon ion treatment

The Treatment planning system (TPS) enables an individual treatment plan to be workedout (dosimetry, irradiation parameters). There is currently none for carbon ion beams thatincludes the biological constraints in a satisfactory way.

A specific approach will be developed from a planning system already existing for protons.Its complexity requires international collaboration, coordinated by IBA, with the INFN(Istituto Nazionale di Fisica Nucleare), and the Elekta company which is already marketingplanning systems worldwide. This carbon TPS will then be tested, validated and optimisedin clinical conditions on the ARCHADE platform.

Clinical research

ARCHADE’s contribution to the clinical field will be restricted to its research activity.

A clinical research protocol specific to carbon ions will be developed in order initially totreat patients with an inoperable radioresistant cancer (ear-nose-throat tumours at thebase of the skull and brain tumours).

This protocol will be validated by the top French health and safety authorities.

ARCHADEEuropean Hadrontherapy Research Centre,in Caen, Normandy

ARCHADE AssociationFrançois Baclesse Centre: Regional Cancer Treatment Centre

CHU: Caen University HospitalENSICaen: National Higher School of Engineering, Caen

University of Caen–Basse Normandie

The Caen Science and Technology Cluster

GANIL: Large National Heavy Ion AcceleratorCYCERON: Biomedical Imaging Centre

L.P.C.: High-Energy Particle Physics LaboratoryLARIA: Host Laboratory for Radiobiology with Accelerated Ions

CIMAP: Ions, Materials & Photonics Research CentreGRECAN: Regional Cancer Research Group

www.archade.frCentre François Baclesse - 3, avenue du général Harris – BP 5026 - 14076 Caen cedex 5