Since 2008, astronomers have been puzzled by a mysterious feature in the cosmic-ray energy spectrum. Data from the PAMELA satellite showed a significant increase in the ratio of positrons to electrons at energies above 10 GeV. This unexpected positron excess was subsequently confirmed by both the Fermi-LAT satellite and the AMS-02 experiment onboard the ISS (CERN Courier December 2016 p26–30), sparking many explanations, ranging from dark-matter annihilation to positron emission by nearby pulsars. New measurements by the High-Altitude Water Cherenkov (HAWC) experiment now seem to rule out the second explanation, hinting at a more exotic origin of the positron excess.
Although standard cosmic-ray propagation models predict the production of positrons from interactions of high-energy protons travelling through the galaxy, the positron fraction is expected to decrease as a function of energy. One explanation for the excess is the annihilation of dark-matter particles with masses of several TeV, which would result in a bump in the electron–positron fraction, with the measured increase perhaps being the rising part of such a bump. According to other models, however, the excess is the result of positron production by astrophysical sources such as pulsars (rapidly spinning neutron stars). Since these charged particles lose energy due to interactions with interstellar magnetic and radiation fields they must be produced relatively close to Earth, making nearby pulsars a prime suspect.
HAWC, situated near the city of Puebla in Mexico, detects charged particles created in the Earth’s atmosphere from collisions between high-energy photons and atmospheric nuclei. The charged particles produced in the resulting shower produce Cherenkov radiation in HAWC’s 300 water tanks, their high altitude location making HAWC the most sensitive survey instrument to measure astrophysical photons in the TeV range. This allows the study of TeV-scale photon emission from nearby pulsars, such as Geminga and PSR B0656+14, to investigate if these objects could be responsible for the positron excess.
Pulsars are thought to emit electrons and positrons with energies up to several hundred TeV, which diffuse into the interstellar medium, but the details of the emission, acceleration and propagation of these leptons are not well understood. The TeV photons measured by HAWC are produced as the electrons and positrons emitted by the pulsars interact with low energy photons in the interstellar medium. One can, therefore, use the intensity of the TeV photon emission and the size of the emitting region to indirectly measure the high-energy positrons. The HAWC data show the large emitting regions of both the pulsars Geminga and PSR B0656+14 (see figure). The spectral and spatial features of the TeV emission were then inserted in a diffusion model for the positrons, allowing the team to calculate the positron flux from these sources reaching Earth. The results, published in Science, indicate that the positron flux from these sources reaching Earth is significantly smaller than that measured by PAMELA and AMS-02.
These indirect measurements of the positron emission appear to rule out a significant contribution of the local positron flux by these two pulsars, making it unlikely that pulsars are the origin of the positron excess. More exotic explanations such as dark matter, or other astrophysical sources such as micro-quasars and supernovae remnants, are not ruled out, however. Results from gamma-ray observations of such sources, along with more detailed measurements of the lepton flux at even higher energies by AMS-02, DAMPE or CALET, are therefore highly anticipated to fully solve the mystery of the cosmic positron excess.
For the past 40 years, CERN’s accelerator complex has been served by a little-known linear accelerator called Linac2. Commissioned in 1978, the 50 MeV linac was constructed to provide a higher beam intensity to the newly built Proton Synchrotron Booster (PSB).
It superseded Linac1, which accelerated its first beam in 1958 and was the only supplier of protons to the CERN Proton Synchrotron (PS) for the following 20 years. Linac1 was sent into retirement in 1992, having spent 33 years accelerating protons as well as deuterons, alpha particles and oxygen and sulphur ions, and is now an exhibit in the CERN Microcosm. Linac3 took over CERN’s ion production in 1994, but today Linac2 is still injecting protons into the PS and SPS from where they end up in the Large Hadron Collider (LHC).
Although the construction of this workhorse of the CERN accelerator chain was an important step forward for CERN, and contributed to major physics discoveries, including the W, Z and Higgs bosons, Linac2’s relatively low energy and intensity are not compatible with the demanding requirements of the LHC luminosity upgrade (HL-LHC). Persistent vacuum problems in the accelerating vessels over the past years also raise major concerns for the performance of the LHC. For this reason, in 2007, it was decided to replace Linac2 with a more suitable injector for the LHC’s future.
A decade later, in spring 2017, the 160 MeV Linac4 was fully commissioned and entered a stand-alone operation run to assess and improve its reliability, prior to being connected to the CERN accelerator complex. The machine’s overall availability during this initial run reached 91 per cent – an amazing value for an accelerator whose beam commissioning was completed only a few months earlier. The Linac4 reliability run will continue well into 2018, sending the beam round-the-clock to a dump located at the end of the accelerating section under the supervision of the CERN Control Centre (CCC) operation team. After a consolidation phase to address any teething troubles identified during the reliability run, Linac4 will be connected to the next accelerator in the chain, the PSB, in 2019 at the beginning of the LHC Long Shutdown 2. Test beams will be made available to the PSB as soon as 2020, and from 2021 all protons at CERN will come from the new Linac4, marking the end of a 20 year-long journey of design and construction that has raised many challenges and inspired innovative solutions.
Linac4 has the privilege of being the only new accelerator built at CERN since the LHC. With an accelerating length of 86 m, plus 76 m of new transfer line, Linac4 is definitely the smallest accelerator in the LHC injection chain. Yet it plays a fundamental role in the preparation of the beam. The linac is where the beam density is generated under the influence of the strong defocusing forces coming from Coulomb repulsion (space charge), and where negative ions initially at rest (containing protons emerging from a bottle of hydrogen gas) are progressively brought close to the relativistic velocities required for acceleration in a synchrotron. This rapid increase in beam velocity requires the use of complex and differentiated mechanical designs to accelerate and focus the beam. Combined with the need for high accelerating gradients (the beam passes only once through the linac), particular demands were placed on Linac4 to achieve the high values of availability required by the first element of the acceleration chain.
The main improvements provided by Linac4 stem from the use of negative hydrogen ions instead of protons and from a higher injection energy into the PSB. Negative hydrogen ions – a proton with two electrons – are converted into protons by passing them through a thin carbon foil, after their injection into the PSB to strip them of electrons. This charge-exchange technique involves progressively injecting the negatively charged ions over the circulating proton beam to achieve a higher particle density. After injection, both beams pass through the stripping foil leaving only protons in the beam. This provides an extremely flexible way to load particles into a synchrotron, making the accumulation of many turns possible with a tight control of the beam density.
Extensive modifications
However, the use of hydrogen ions does not come without complications. It requires extensive modifications to the injection area of the synchrotron and a complex ion source in front of the linac. The other key element for generating the high-brightness beams required by the LHC upgrade is the increase of the injection energy in the PSB by more than a factor three with respect to the present Linac2, which reduces space-charge effects at the PSB injection and allows the accumulation of more intense beams.
On top of these crucial advantages for the HL-LHC, Linac4 is designed to be more flexible and more environmentally clean than Linac2. Modulation at low energy of the beam-pulse structure, the option of varying beam energy during injection and a useful margin in the peak beam current will help prepare the large variety of beams required by the injector complex, at the same time reducing beam loss and activation in the PSB. Linac4 is also designed for the long term. Having originated from studies at the end of the 1990s, the goal was to progressively replace the PS complex (Linac2, PSB and PS) with more modern accelerators capable of higher intensities for the future needs of the LHC and other non-LHC programmes. Alas, this ambitious staged approach was later discarded to give priority to the consolidation of CERN’s older synchrotrons, but Linac4 retains features related to the old staged programme that could be exploited to adapt the CERN injector complex to future physics programmes. Examples are the orientation of the Linac4 tunnel, which leaves space for future extensions to higher energies, and its pulse-repetition frequency. The latter is currently limited by the rise time of the PSB magnets to about 1 Hz, but this could be upgraded up to 50 Hz were the PSB to be replaced one day by another accelerator.
Last but not least, Linac4 is a model for the successful reuse of old equipment. All its accelerating structures operate at a frequency of 352 MHz, which is precisely that of the old Large Electron Positron (LEP) collider. Linac4 reuses a large quantity of LEP’s RF components, such as klystrons and waveguides, which were carefully stored and maintained following LEP’s closure in 2000. However, the LEP klystrons installed in Linac4 will gradually be replaced in pairs by modern klystrons with twice the power.
Reaching Linac4’s required performance and reliability posed several problems in the design and construction of the new linac. The first challenge was to build a reliable source of negative hydrogen ions, starting from a new design developed at CERN that profited from the experience of other laboratories such as DESY and Brookhaven National Laboratory. The ion source is a complex device that starts from a bottle of hydrogen similar to the one used in Linac2 and generates ions in a plasma heated by a high-frequency wave of several dozen kilowatts. Following some initial difficulties, the new ion source is now steadily providing the minimum beam intensity required by the LHC, while improvements are still ongoing.
Accelerating elements
After the ion source, the challenge for the main Linac4 accelerating section has been to integrate focusing and accelerating elements in the small linac cells, achieving a good power efficiency at the same time. These requirements motivated the use of four different types of accelerating structure: an RF quadrupole (RFQ)to take the energy to 3 MeV; a drift-tube linac (DTL) of the Alvarez type to 50 MeV; a cell-coupled drift-tube linac (CCDTL) to 102 MeV; and finally a Pi-mode structure (PIMS) to the final energy of 160 MeV. Most of these accelerating sections include important innovations. The CCDTL and PIMS structures are a world-first developed specifically for Linac4 and used for the first time to accelerate a beam. The DTL includes a novel patented mechanism to support and adjust the drift tubes and makes use for the first time at CERN of a long focusing section made of 108 permanent magnet quadrupoles. To these innovations we had to add a novel scheme to “chop” the beam pulse at low energy, a simplified RFQ mechanical design, and finally the flexible and upgradeable beam optics design.
In spite of a general trend towards superconducting accelerators, Linac4 is entirely normal-conducting. This is a logical choice for a low-energy linear accelerator injecting into a synchrotron and operating at low duty cycle. Linac4 is pulsed, and the short particle beam is in the linac only for a tiny fraction of time. Although as much as 24 MW of RF power are needed for acceleration during the beam pulse, the average power to the accelerating structures will be only 8 kW, out of which only about 6 kW are dissipated in the copper, the rest going to the beam. The power required to cool Linac4 to cryogenic temperatures would be much higher than the power lost into the copper structures.
The construction of Linac4 is a great example of international collaboration, expanding well beyond the boundaries of CERN. Already in the R&D phase between 2004–2008, Linac4 collected support from the European Commission and a group of Russian institutes supported by the ISTC international organisation. The construction of the accelerator received important contributions from a large number of collaborating institutes. These included CEA and CNRS in France, BINP and VNIITF in Russia, NCBJ in Poland, ESS Bilbao in Spain, INFN in Italy and RRCAT in India. Organising this wide network of collaborations was a great challenge, but the results were excellent both in terms of technical quality of the components and in terms of developing a common working culture.
Linac4 brought proton-linac technology back to Europe. Since the construction of Linac2 in 1978 and of the HERA injector at DESY a few years later, all new proton linac developments took place in the US and in Japan. The development effort coordinated by CERN for the construction of Linac4 allowed bringing back to Europe the latest developments in linac technology described above, with a strong involvement of European companies. A measure of the success of this endeavour is the fact that many technical solutions developed for Linac4 will be now adopted by the normal-conducting section of the new European Spallation Source linac under construction at Lund, Sweden.
The inauguration of Linac4 on 9 May 2017 marked the coronation of a long project. The ground-breaking on so-called “Mount Citron” (made in the 1950s with the spoil from the construction of the PS ring) took place in October 2008 and the new linac building started to take shape. Construction extended over the mandate of three CERN Directors General. It’s expected that Linac4 will have a long life – at least as long as Linac2 – and play a vital role at the high-luminosity LHC and beyond.
Last September the TERA Foundation – dedicated to the study and development of accelerators for particle therapy – celebrated its 25th anniversary. Led by visionary Italian physicist Ugo Amaldi, TERA gathered and trained hundreds of brilliant scientists who carried out research on accelerator physics. This culminated in the first carbon-ion facility for hadron therapy in Italy, and the second in Europe: the National Centre for Cancer Hadron Therapy (CNAO), located in Pavia, which treated its first patient in 2011.
The forerunner to CNAO was the Heidelberg Ion-Beam Therapy Centre (HIT) in Germany, which treated its first patient in 2009 following experience accumulated over 12 years in a pilot project at GSI near Darmstadt. After CNAO came the Marburg Ion-Beam Therapy Centre (MIT) in Germany, which has been operational since 2015, and MedAustron in Wiener Neustadt, Austria, which delivered its first treatment in December 2016.
While conventional radiotherapy based on beams of X-rays or electrons is already widespread worldwide, the treatment of cancer with charged particles has seen significant growth in recent years. The use of proton beams in radiation oncology was first proposed in 1946 by Robert Wilson, a student of Ernest Lawrence and founding director of Fermilab. The key advantage of proton beams over X-rays is that the absorption profile of protons in matter exhibits a sharp peak towards the end of their path, concentrating the dose on the tumour target while sparing healthy tissues. Following the first treatment of patients with protons at Lawrence Berkeley Laboratory in the US in 1954, treatment centres in the US, the former USSR and Japan gradually appeared. At the same time, interest arose around the idea of using heavier ions, which offer a higher radio-biological effectiveness and, causing more severe damage to DNA, can control the 3% of all tumours that are radioresistant both to X-rays and protons. It is expected that by 2020 there will be almost 100 centres delivering particle therapy around the world, with more than 30 of them in Europe (see “The changing landscape of cancer therapy”).
Europe entered the hadron-therapy field in 1987, when the European Commission launched the European Light Ion Medical Accelerator (EULIMA) project to realise a particle-therapy centre. The facility was not built in the end, but interest in the topic continued to grow. In 1991, together with Italian medical physicist Giampiero Tosi, Amaldi wrote a report outlining the design of a hospital facility for therapy with light ions and protons to be built in Italy. One year later, the pair established the TERA Foundation to raise the necessary funding to employ students and researchers to work on the project. Within months, TERA could count on the work of about 100 physicists, engineers, medical doctors and radiobiologists, who joined forces to design a synchrotron for particle therapy and the beamlines and monitoring systems necessary for its operation.
Ten years of ups and downs followed, during which TERA scientists developed three designs for a proton-therapy facility initially to be built in Novara, then in the outskirts of Milan and finally in Pavia. Political, legislative and economic issues delayed the project until 2001 when, thanks to the support of Italian health minister and oncologist Umberto Veronesi, the CNAO Foundation was created. The construction of the actual facility began four years later.
“We passed through hard times and we had to struggle, but we never gave up,” says Amaldi. “Besides, we kept ourselves busy with improving the design of our accelerator.”
Meanwhile, in Austria, experimental physicist Meinhard Regler had launched a project called Austron – a sort of precursor to the European Spallation Source. In 1995, together with the head designer – accelerator physicist Phil Bryant – he proposed the addition of a ring to the facility that would be used for particle therapy (and led to the name of the project being changed to MedAustron). Amaldi, Regler and Bryant then decided to work on a common project, and the “Proton-Ion Medical Machine Study” (PIMMS) was created. Developed at CERN between 1996 and 2000 under the leadership of Bryant and with the collaboration of several CERN physicists and engineers, PIMMS aimed to be a toolkit for any European country interested in building a proton–ion facility for hadron therapy. Rather than being a blueprint for a final facility on a specific site, it was an open study from which different parts could be included in any hadron-therapy centre according to its specific needs.
The design of CNAO itself is based on the PIMMS project, with some modifications introduced by TERA to reduce the footprint of the structure. The MedAustron centre, designed in the early 2000s, also drew upon the PIMMS report. Built between 2011 and 2013, with the first beam extracted by the synchrotron in autumn 2014, MedAustron received official certification as a centre for cancer therapy in December 2016 and, a few days after, treated its first patient. “In the past few years we have worked hard to provide the MedAustron trainees with a unique opportunity to acquire CERN’s know-how in the diverse fields of accelerator design, construction and operation,” says Michael Benedikt of CERN, who led the MedAustron accelerator project. Synergies with other CERN projects were also created, he explains. “The vacuum control system built for MedAustron was successfully used in the Linac4 test set-up, while in the synchrotron a novel radiofrequency system that was jointly developed for the CERN PS Booster and MedAustron is used. The synchrotron’s power converter control uses the same top-notch technology as CERN’s accelerators, while its control system and several of its core components are derived from technologies developed for the CMS experiment.”
All the existing facilities using hadrons for cancer therapy are based on circular cyclotrons and synchrotrons. For some years, however, the TERA Foundation has been working on the design of a linear accelerator for hadron therapy. As early as 1993, Amaldi set up a study group, in collaboration with the Italian institutions ENEA and INFN, dedicated to the design of a linac for protons that would run at the same frequency (3 GHz) as the electron linacs used for conventional radiotherapy. The linac could use a cyclotron as an injector, making it a hybrid solution called a cyclinac, which reduces the sizes of both accelerators while allowing the beam energy to be rapidly changed from pulse to pulse by acting on the radiofrequency system of the linac. In 1998 a 3 GHz 1.2 metre-long linac booster (LIBO) was built by a TERA–CERN–INFN collaboration led by retired CERN engineer Mario Weiss, and in 2001 it was connected to the cyclotron of the INFN South Laboratories in Catania where it accelerated protons from 62 MeV to 74 MeV. This was meant to be the first of 10 modules that would kick protons to 230 MeV.
Linear ambition
In 2007 a CERN spin-off company called ADAM (Applications of Detectors and Accelerators to Medicine) was founded by businessman Alberto Colussi to build a commercial high-frequency linac based on the TERA design. Under the leadership of Stephen Myers, a former CERN director for accelerators and technology and initiator of the CERN medical applications office, ADAM is now completing the first prototype. It is called Linac for Image Guided Hadron Therapy (LIGHT), and the full accelerator comprises: a proton source; a novel 750 MHz RF quadrupole (RFQ) – designed by CERN – which takes the particles up to 5 MeV; four side-coupled drift-tube linacs (SCDTL) – designed by ENEA – to accelerate the beam from 5–37.5 MeV; and a different type of accelerating module, called coupled-cavity linac (CCL) – the LIBO designed by TERA – which gives the final kick to the beam from 37.5 to 230 MeV. The complex will be 24 m long, similar to the circumference of a proton synchrotron.
Compared to cyclotrons and synchrotrons, linear accelerators are lighter and potentially less costly because they are modular. Most importantly, they produce a beam much more suited to treat patients, in particular when the tumour is moving, as in the lungs. The machine developed by ADAM is modular in structure to make it easier to maintain and more flexible when it comes to upgrading or customising the system. In addition, thanks to an active longitudinal modulation system, the beam energy can be varied during therapy and thus the treatment depth changed. LIGHT also has a dynamic transversal modulation system, allowing the beam to be rapidly and precisely modulated to “paint the tumour” many times in a short time – in other words, delivering a homogeneous dose to the whole cancerous tissue while minimising the irradiation of healthy organs. The energy variation of cyclotrons and synchrotrons is 20–100 times slower.
“The beauty of the linac is that you can electronically modulate its output energy,” Myers explains. “Since our accelerator is modular, the energy can be changed either by switching off some of the units or by reducing the power in all of them, or by re-phasing the units. Another big advantage of the linac is that it has a small emittance, i.e. beam size, which translates into smaller, lighter and cheaper magnets and allows to have a simpler and lighter gantry as well.” In the last decade, LIBO has inspired other TERA projects. Its scientists have designed a linac booster for carbon ions (while LIBO was only for protons) and a compact single-room facility called TULIP, in which a 7 m-long proton linac is mounted on a rotating gantry.
The new frontier of hadron therapy, however, could be helium ion treatment. Some tests with these ions were done in the past, but the technique still has to be proven. TERA scientists are currently working on a new accelerator for helium ions, says Amaldi. “Helium can bring great benefit to medical treatments: it is lighter than carbon, thus requiring a smaller accelerator, and it has much less lateral scattering than protons, resulting in sharper lateral fall-offs next to organs at risk.” In order to accelerate helium ions with a linac, we need either a longer linac compared to the one used for protons or higher gradients, as demonstrated by high-energy physics research at CERN and elsewhere in Europe. The need for future, compact and cost-effective ion-therapy accelerators is being addressed by a new collaborative design study coordinated by Maurizio Vretenar and Alessandra Lombardi of CERN, dubbed “PIMMS2”. A proposal, which includes a carbon linac, is being prepared for submission to the CERN Medical Application group, potentially opening the next phase of TERA’s impressive journey.
The use of radioisotopes to treat cancer goes back to the late 19th century, with the first clinical trials taking place in France and the US at the beginning of the 20th century. Great strides have been made, and today radioisotopes are widely used by the medical community. Produced mostly in dedicated reactors, radioisotopes are used in precision medicine, both to diagnose cancers and other diseases, such as heart irregularities, as well as to deliver very small radiation doses exactly where they are needed to avoid destroying the surrounding healthy tissue.
However, many currently available isotopes do not combine the most appropriate physical and chemical properties and, in the case of certain tumours, a different type of radiation could be better suited. This is particularly true of the aggressive brain cancer glioblastoma multiforme and of pancreatic adenocarcinoma. Although external beam gamma radiation and chemotherapy can improve patient survival rates, there is a clear need for novel treatment modalities for these and other cancers.
On 12 December, a new facility at CERN called MEDICIS produced its first radioisotopes: a batch of terbium (155Tb), which is part of the 149/152/155/161Tb family considered a promising quadruplet suited for both diagnosis and treatment. MEDICIS is designed to produce unconventional radioisotopes with the right properties to enhance the precision of both patient imaging and treatment. It will expand the range of radioisotopes available – some of which can be produced only at CERN – and send them to hospitals and research centres in Switzerland and across Europe for further study.
Initiated in 2010 by CERN with contributions from the Knowledge Transfer Fund, private foundations and partner institutes, and also benefitting from a European Commission Marie Skłodowska-Curie training grant titled MEDICIS-Promed, MEDICIS is driven by CERN’s Isotope Mass Separator Online (ISOLDE) facility. ISOLDE has been running for 50 years, producing 1300 different isotopes from 73 chemicals for research in many areas including fundamental nuclear research, astrophysics and life sciences.
Although ISOLDE already produces isotopes for medical research, MEDICIS will more regularly produce isotopes with specific types of emission, tissue penetration and half-life – all purified based on expertise acquired at ISOLDE. This will allow CERN to provide radioisotopes meeting the requirements of the medical research community as a matter of course.
ISOLDE directs a high-intensity proton beam from the Proton Synchrotron Booster onto specially developed thick targets, yielding a large variety of atomic fragments. Different devices are used to ionise, extract and separate nuclei according to their masses, forming a low-energy beam that is delivered to various experimental stations. MEDICIS works by placing a second target behind ISOLDE’s: once the isotopes have been produced on the MEDICIS target, an automated conveyor belt carries them to a facility where the radioisotopes of interest are extracted via mass separation and implanted in a metallic foil. The final product is then delivered to local research facilities including the Paul Scherrer Institute, the University Hospital of Vaud and Geneva University Hospitals.
Clinical setting
Once in a medical-research environment, researchers dissolve the isotope and attach it to a molecule, such as a protein or sugar, which is chosen to target the tumour precisely. This makes the isotope injectable, and the molecule can then adhere to the tumour or organ that needs imaging or treating. Selected isotopes will first be tested in vitro, and in vivo by using mouse models of cancer. Researchers will test the isotopes for their direct effect on tumours and when they are coupled to peptides with tumour-homing capacities, and establish new delivery methods for brachytherapy using stereotactic or robotic-assisted surgery in large-animal models for their capacity to target glioblastoma or pancreatic adenocarcinoma or neuroendocrine tumour cells.
MEDICIS is not just a world-class facility for novel radioisotopes. It also marks the entrance of CERN into the growing field of theranostics, whereby physicians verify and quantify the presence of cellular and molecular targets in a given patient with a diagnostic radioisotope, before treating the disease with the therapeutic radioisotope. The prospect of a dedicated facility at CERN for the production of innovative isotopes, together with local leading institutes in life and medical sciences and a large network of laboratories, gives MEDICIS an exciting scientific programme in the years to come. It is also a prime example of the crossover between fundamental physics research and health applications, with accelerators set to play an increasing role in the production of life-changing medical isotopes.
Cancer is a critical societal issue. Worldwide, in 2012 alone, 14.1 million cases were diagnosed, 8.2 million people died and 32.5 million people were living with cancer. These numbers are projected to rise by 2030 to reach 24.6 million newly diagnosed patients and projected deaths of 13 million. While the rate of cancer diagnoses is growing only steadily in the most developed countries, less developed countries can expect a two-fold increase in the next 20 years or so. The growing economic burden imposed by cancer – amounting to around $2 trillion worldwide in 2010 – is putting considerable pressure on public healthcare budgets.
Radiotherapy, in which ionising radiation is used to control or kill malignant cells, is a fundamental component of effective cancer treatment. It is estimated that about half of cancer patients would benefit from radiotherapy for treatment of localised disease, local control, and palliation. The projected rise in cancer cases will place increased demand on already scarce radiotherapy services worldwide, particularly in less developed countries.
In 2013, member states of the World Health Organisation agreed to develop a global monitoring framework for comprehensive, non-communicable diseases (NCDs). The aim is to reduce premature mortality from cardiovascular and chronic respiratory diseases, cancers and diabetes by 25%, relative to 2010 levels, which means 1.5 million deaths from cancer will need to be prevented each year.
Advanced cancer therapy techniques based on beams of protons or ions are among several tools that are expected to play a significant role in this effort (see “Therapeutic particles”). In addition, advanced imaging and detection technologies for high-energy physics research – many being driven by CERN and the physics community – are needed. These include in-beam positron emission tomography (PET) and prompt-gamma imaging, and treatment planning based on the latest Monte Carlo simulation codes.
The main goal of radiotherapy is to maximise the damage to the tumour while minimising the damage to the surrounding healthy tissue, thereby reducing acute and late side effects. The most frequently used radiotherapy modalities use high-energy (MeV) photon or electron beams. Conventional X-ray radiation therapy is characterised by almost exponential attenuation and absorption, delivering the maximum energy near the beam entrance, but continuing to deposit significant energy at distances beyond the cancer target. The maximum energy deposition, for X-ray beams with energy of about 8 MeV, is reached at a depth of 2–3 cm in soft tissue. To deliver dose optimally to the tumour, while protecting surrounding healthy tissues, radiotherapy has progressed rapidly with the development of new technologies and methodologies. The latest developments include MRI-guided radiotherapy, which combines simultaneous use of MRI-imaging and photon irradiation. Such advanced radiation therapy modalities are becoming increasingly important and offer new opportunities to treat different cancers, in particular the combination with other emerging areas such as cancer-immunotherapy and the integration of sequencing data, with clinical-decision support systems for personalised medicine.
However, if one looks at the dose deposition profile of photons compared to other particles (figure 1), the conspicuous feature of this graph is that, in the case of protons and carbon ions, a significant fraction of the energy is deposited in a narrow depth range near the endpoint of the trajectory, after which very little energy is deposited. It was precisely these differences in dose – the so-called Bragg-peak effect – that led visionary physicist and founder of Fermilab, Robert Wilson, to propose the use of hadrons for cancer treatment in 1946.
Hadron or particle therapy is a precise form of radiotherapy that uses charged particles instead of X-rays, to deliver a dose of radiotherapy to patients. Radiation therapy with hadrons or particles (protons and other light ions) offers several advantages over X-rays: not only do hadrons and particles deposit most of their energy at the end of their range, but particle beams can be shaped with great precision. This allows for more accurate treatment of the tumour, destroying the cancer cells more precisely with minimal damage to surrounding tissue. Radiotherapy using the unique physical and radiobiological properties of charged hadrons, also allows highly conformal treatment of various kinds of tumours, in particular those that are radio-resistant.
Over the past two decades, particle-beam cancer therapy has gained huge momentum. Many new centres have been built, and many more are under construction (figure 2). At the end of 2016 there were 67 centres in operation worldwide and another 63 are in construction or in the planning stage. Most of these are proton centres: 25 in US (protons only); 19 in Europe (three dual centres); 15 in Japan (four carbon and one dual); three (one carbon and one dual) in China; and four in other parts of the world. By 2021 there will be 130 centres operating in nearly 30 countries. European centres are shown in figure 3, while figure 4 shows that the cumulated number of treated patients is growing almost exponentially.
At the end of 2007, 61,855 patients had been treated (53,818 with protons and 4,450 with carbon ions). At the end of 2016 the number had grown to 168,000 (145,000 with protons and 23,000 with carbon ions). This is due primarily to the greater availability of dedicated centres able to meet the growing demand for this particular form of radiotherapy, and most probably in future it will have a larger growth rate, with an increase of the patient throughput per centre.
Particle-physics foundation
High-energy physics research has played a major role in initiating, and now expanding, the use of particle therapy. The first patient was treated at Berkeley National Laboratory in the US with hadrons in September 1954 – the same year CERN was founded – and was made possible by the invention of the cyclotron by Ernest Lawrence and subsequent collaboration with his medical-doctor brother, John. The first hospital-based, particle-therapy centres opened in 1989 atClatterbridge in the UK and in 1990 at the Loma Linda University Medical Center in the US. Before this time, all research related to hadron therapy and patient treatment was carried out in particle-physics labs.
In addition to the technologies and research facilities coming from the physics community, the culture of collaboration at the heart of organisations such as CERN is finding its way into other fields. This has inspired the European Network for Light Ion Therapy (ENLIGHT) to promote international discussions and collaboration in the multidisciplinary field of hadron therapy, which has now been running for 15 years (see “Networking against cancer”).
Were it not for the prohibitively large cost of installing proton-therapy treatment in hospitals, it would be the treatment of choice for most patients with localised tumours. Proton-therapy technology is significantly more compact today than it once was, but when combined with the gantry and other necessary equipment, even the most compact systems on the market occupy an area of a couple of hundred square metres. Most hospitals lack the financial resources and space to construct a special building for proton therapy, so we need to make facilities smaller and cheaper, with costs of around $5–10 million for a single room, similar to state-of-the-art photon-therapy systems. An ageing population, and the need for a more patient-specific approach to cancer treatment and other age-related diseases, present major challenges for future technologies to control rising health costs, while continuing to deliver better outcomes for patients. Scientists working at the frontiers of particle physics have much to contribute to these goals, and the culture of collaboration will ensure that breakthrough technologies find their way into the medical clinics of the future.
If you live in a low- or middle-income country (LMIC), your chances of surviving cancer are significantly lower than if you live in a wealthier economy. That’s largely due to the availability of radiation therapy (see “The changing landscape of cancer therapy”). Between 2015 and 2035, the number of cancer diagnoses worldwide is expected to increase by 10 million, with around 65% of those cases in poorer economies. Approximately 12,600 new radiotherapy treatment machines and up to 130,000 trained oncologists, medical physicists and technicians will be needed to treat those patients.
Experts in accelerator design, medical physics and oncology met at CERN on 26–27 October 2017 to address the technical challenge of designing a robust linear accelerator (linac) for use in more challenging environments. Jointly organised by CERN, the International Cancer Expert Corps (ICEC) and the UK Science and Technology Facilities Council (STFC), the workshop was funded through the UK Global Challenges Research Fund, enabling participants from Botswana, Ghana, Jordan, Nigeria and Tanzania to share their local knowledge and perspectives. The event followed a successful inaugural workshop in November 2016, also held at CERN (CERN Courier March 2017 p31).
The goal is to develop a medical linear accelerator that provides state-of-the-art radiation therapy in situations where the power supply is unreliable, the climate harsh and/or communications poor. The immediate objective is to develop work plans involving Official Development Assistance (ODA) countries that link to the following technical areas (which correspond to technical sessions in the October workshop): RF power systems; durable and sustainable power supplies; beam production and control; safety and operability; and computing.
Participants agreed that improving the operation and reliability of selected components of medical linear accelerators is essential to deliver better linear accelerator and associated instrumentation in the next three to seven years. A frequent impediment to reliable delivery of radiotherapy in LMICs, and other underserved regions of the world, is the environment within which the sophisticated linear accelerator must function. Excessive ambient temperatures, inadequate cooling of machines and buildings, extensive dust in the dry season and the high humidity in some ODA countries are only a few of the environmental factors that can challenge both the robustness of treatment machines and the general infrastructure.
Simplicity of operation is another significant factor in using linear accelerators in clinics. Limiting factors to the development of radiotherapy in lower-resourced nations don’t just include the cost of equipment and infrastructure, but also a shortage of trained personnel to properly calibrate and maintain the equipment and to deliver high-quality treatment. On one hand, the radiation technologist should be able to set treatments up under the direction of the radiation oncologist and in accordance with the treatment plan. On the other hand, maintenance of the linear accelerators should also be as easy as possible – from remote upgrades and monitoring to anticipate failure of components. These centres, and their machines, should be able to provide treatment on a 24/7 basis if needed, and, at the same time, deliver exclusive first-class treatment consistent with that offered in richer countries. STFC will help to transform ideas and projects presented in the next workshop, scheduled for March 2018, into a comprehensive technology proposal for a novel linear accelerator. This will then be submitted to the Global Challenges Research Fund Foundation Awards 2018 call for further funding. This ambitious project aims to have facilities and staff available to treat patients in low- and middle-income countries within 10 years.
The inaugural meeting of the European Network for Light Ion Hadron Therapy (ENLIGHT) took place at CERN in February 2002, with the aim of co-ordinating European efforts in innovative cancer treatment strategies using radiation. Specialists from different disciplines, including radiation biology, oncology, physics and engineering, with experience and interest in particle therapy have nurtured the network ever since.
Today, ENLIGHT can count on the contribution of more than 700 members from all continents. Together, they identify and tackle the technical challenges related to the use of highly sophisticated machines, train young and specialist researchers, and seek funding to ensure the sustainability and effectiveness of the organisation.
Started with the support of the European Commission (EC), ENLIGHT has coordinated four other EC projects in particle therapy: ULICE, PARTNER, ENVISION and ENTERVISION. In the past 15 years, the network has evolved into an open, collaborative and multidisciplinary platform to establish priorities and assess the effectiveness of various treatment modalities. Initially based on the three technologies and innovation pillars – accelerators, detectors and computing – of high-energy physics, the ENLIGHT initiative has evolved into a global effort.
Training essential
ENLIGHT has witnessed a large increase in dedicated particle therapy centres, and innovative medical imaging techniques are starting to make their way into hospitals. Skilled experts for high-tech cancer treatment are, therefore, in high demand. Thanks to the large number of scientists involved and its wide reach, ENLIGHT has enormous potential to offer education and training and, since 2015, has included training sessions in its annual meetings.
Education and training, in addition to pitching for research funding, are the main thrusts of ENLIGHT’s activities today. A project within the CERN & Society Foundation has just been approved, opening a new chapter for ENLIGHT and its community. The benefits lie, not only in reinforcing the hadron therapy field with qualified multidisciplinary groups of experts, but especially in helping young scientists flourish in the future.
Innovative ideas and technologies from physics have contributed to great advances in medicine, in particular radiation-based medical diagnosis and treatment. Today, state-of-the-art techniques derived from particle physics research are routinely used in clinical practice and medical research centres: from technology for PET scanners and dedicated accelerators for cancer therapy (see The changing landscape of cancer therapy), to simulation and data analysis tools.
Transferring CERN’s know-how to other fields is an integral part of its mission. Over the past 60 years, CERN has developed widely recognised expertise and unique competencies in particle accelerators, detectors and computing. While CERN’s core mission is basic research in particle physics, these “tools of the trade” have found applications in a variety of fields and can have an impact far beyond their initial expectations. An excellent recent example is the completion of CERN MEDICIS, which uses a proton beam to produce radioisotopes for medical research (see “Isotopes for precision medicine”).
Knowledge transfer (KT) for the benefit of medical applications has become an established part of CERN’s programme, formalised within the KT group. CERN has further initiated numerous international and multidisciplinary collaborations, partially or entirely devoted to technologies with applications in the medical field, some of which have been funded by the European Commission (EC). Until recently, the transfer of knowledge and technology from physics to medicine at CERN has essentially been driven by enthusiastic individuals on an ad hoc basis. In light of significant growth in medical applications-related activities, in 2017 CERN published a formal medical applications strategy (approved by the Council in June).
Its aims are to ensure that medical applications-related knowledge transfer activities are carried out without affecting CERN’s core mission of fundamental research, are relevant to the medical community and delivered within a sustainable funding model.
The focus is on R&D projects using technologies and infrastructures that are uniquely available at CERN, seeking to minimise any duplication of efforts taking place in Member States and associate Member States. The most promising CERN technologies and infrastructure that are relevant to the medical domain shall be identified – and the results matched with the requirements of the medical research communities, in particular in CERN’s Member States and associate Member States. Projects shall then be identified, taking into account such things as: maximising the impact of CERN’s engagement; complementarities with work at other laboratories; and the existence of sufficient external funding and resources.
CERN’s medical applications-related activities are co-ordinated by the CERN KT medical applications section, which also negotiates the necessary agreements with project partners. A new KT thematic forum, meanwhile, brings together CERN and Member State representatives to exchange information and ideas about medical applications (see “Faces and Places”). The CERN Medical Applications Steering Committee (CMASC) selects, prioritises, approves and coordinates all proposed medical applications-related projects. The committee receives input from the Medical Applications Project Forum (MAPF), the CERN Medical Applications Advisory Committee (CMAAC) and various KT bodies.
Although CERN can provide a limited amount of seed funding for medical applications projects, external stakeholders must provide the funding needed to deliver their project. Additional funding may be obtained through the EC Framework Programmes, and the CERN & Society Foundation is another potential source.
The transfer of know-how and technologies from CERN to the medical community represents one of the natural vehicles for CERN to disseminate the results of its work to society as widely as possible. The publication of a formal strategy document represents an important evolution of CERN’s program and highlights its commitment to maximise the societal impact of its research and to transfer CERN’s know-how and technology to its Member States and associate Member States.
Ranging from classical to quantum mechanics, from nuclear to particle physics and cosmology, this book aims to provide an overview of various branches of physics in both a comprehensive and concise fashion. As the authors state, their objective is to offer an inspirational tour of fundamental physics that is accessible to readers with a high-school background in physics and mathematics, and to motivate them to delve deeper into the topics covered.
Key equations are presented and their solutions derived, ensuring that each step is clear. Emphasis is also placed on the use of variational principles in physics.
After introducing some basic ideas and tools in the first chapter, the book presents Newtonian dynamics and the application of Newton’s law of gravitation to the motion of bodies in the solar system. Chapter 3 deals with the electromagnetic field and Maxwell’s equations. From classical physics, the authors jump to Einstein’s revolutionary theory of special relativity and the concept of space–time. Chapters 5 and 6 are devoted to curved space, general relativity and its consequences, including the existence of black holes. The other revolutionary idea of the 20th century, quantum mechanics, is discussed in chapters 7 and 8, while chapter 9 applies this theory to the structure and properties of materials, and explains the fundamental principles of chemistry and solid-state physics. Chapter 10 covers thermodynamics, built on the concepts of temperature and entropy, and gives special attention to the analysis of black-body radiation. After an overview of nuclear physics (chapter 11), chapter 12 presents particle physics, including a short description of quantum field theory, the Standard Model with the Higgs mechanism and the recent discovery of its related boson. Chapters 13 and 14 are about astrophysics and cosmology, while the final chapter discusses some of the fundamental problems that remain open.
This book by Katherine Freese, now out in paperback, is aimed at non-professionals interested in dark matter. The hypothesis that the matter in galaxy clusters is dominated by a non-luminous component, and hence is dark, goes back to a paper published in 1933 by the Swiss astronomer Fritz Zwicky, who also coined the term “dark matter”. But it has only been during the last 20 years or so that we have realised that the matter in the universe is dominated by dark matter and that most of it is non-baryonic, i.e. not made of the stuff that makes up all the other matter we know.
The author explains the observational evidence for dark matter and its relevance for cosmology and particle physics, both in a formal scientific context and also based on her personal adventures as a researcher in this field. I especially enjoyed her detailed, well-informed discussion and evaluation of present dark-matter searches.
The book is structured in nine chapters. The first is a personal introduction, followed by a historical account of the growing evidence for dark matter. Chapter 3 discusses our present understanding of the expanding universe, explaining how much of what we know is due to the very accurate observations of the cosmic microwave background. This is followed by a chapter on Big Bang nucleosynthesis, describing how the first elements beyond hydrogen (deuterium, helium-3, lithium and especially helium-4) were formed in the early universe. In the fifth chapter, the plethora of dark-matter candidates – ranging from axions to WIMPS and primordial black holes – are presented. Chapter 6 is devoted to the LHC at CERN: its four experiments are briefly described and the discovery of the Higgs is recounted. Chapters 6 and 7 are at the heart of the author’s own research (the author is a dark-matter theorist and not heavily involved in any particular dark-matter experiments). They discuss the experiments that can be undertaken to detect dark matter, either directly or indirectly or via accelerator experiments. An insightful and impartial discussion of present experiments with tentative positive detections is presented in chapter 8. The final chapter is devoted to dark energy, responsible for the accelerated expansion of the universe. Is it a cosmological constant or vacuum energy with a value that is many orders of magnitude smaller than what we would expect from quantum field theory? Is it a dynamical field or does the beautiful theory of general relativity break down at very large distances?
Even though in some places inaccuracies have slipped in, most explanations are rigorous yet non-technical. In addition to the fascinating subject, the book contains a lot of interesting personal and historical remarks (many of them from the first- or second-hand experience of the author), which are presented in an enthusiastic and funny style. They are one of the characteristics that make this book not only an interesting source of information but also a very enjoyable read.
As a female scientist myself, I appreciated the way the author acknowledges the work of women in science. She presents a picture of a field of research that has been shaped by many brilliant female scientists, starting from Vera Rubin’s investigations of galaxy rotation curves and ending with Elena Aprile’s and Laura Baudis’ lead in the most advanced direct dark-matter searches. It seems to need a woman to do justice to our outstanding female colleagues.
The fact that less than three years after the first publication of the book some cosmological parameters have shifted and some information about recent experiments is already outdated only tells us that dark matter is a hot topic of very active research. I sincerely hope that the author’s gut feeling is correct and the discovery of dark matter is just around the corner.
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