1 Introduction

Boron Neutron Capture Therapy (BNCT) is an experimental method of hadron therapy that involves irradiating cancer cells with neutrons followed by perfusion with a boron compound capable of concentrating 10B atoms in cancer cells. The thermal-neutron capture event on 10B is extremely likely to produce two ionizing particles: an α particle and a 7 Li ion. These particles lose all of their energy over a distance similar to a cell's diameter and can cause irreparable DNA damage as they pass through the nucleus. If enough boron is taken by tumor cells, resulting in a high boron concentration ratio between tumour and healthy cells, neutron irradiation may give a therapeutic dosage to the tumour while sparing the healthy tissues. The selectivity of this therapy is based on the bio-distribution of boron, rather than on the irradiation field. This makes the BNCT a suitable option for the treatment of diffuse tumours since the neutron irradiation of the entire organ would affect all tumour nodules without the need to know their number, distribution or shape [1].

The development of accelerator-based neutron sources, replacing nuclear reactors, represents the most important recent innovation in the field of BNCT [2]; for this reason, this technique and its application to new tumours is being deployed in hospital environment. Figure 1 depicts the Tandem accelerator manufactured by the American firm TAE Life Sciences (TLS). TLS and CNAO have signed a partnership agreement that will supply the accelerator, beamlines, beam shaping assembly (BSA), and patient placement for the BNCT at CNAO. For the first time in Italy, a compact particle accelerator for producing neutron beams will be placed in a specialized area to support clinical and scientific operations.

Fig. 1
figure 1

Tandem accelerator with source (on the left) and beamlines. The proton beam energy is 2.5 MeV and the intensity is 10 mA (courtesy of TLS-TAE Life Sciences)

Full size image

In the history of BNCT, Pavia has had an impact. Since the 1980s, researchers have been studying BNCT, making use of the laboratory of applied nuclear energy (LENA) which has a nuclear research reactor available for use. Ex-situ BNCT was used to treat livers of two patients (2001 and 2003) with very interesting results [3, 4]. The research efforts of the University of Pavia groups, in collaboration with INFN and other partner institutes, have been greatly enhanced and sustained by this experience.

The National Centre for Oncological Hadrontherapy (CNAO) is a facility sited in Pavia that treats patients with hadron beams [5]. The CNAO Foundation, a not-for-profit entity, has been created in 2001 by the Italian Ministry of Health to introduce hadrontherapy in clinics and pursue related research activities. The Board of CNAO is formed by public and private institutions: the Founders, namely two large University hospitals (Ospedale Maggiore in Milan and San Matteo in Pavia), two oncological hospitals (the public Istituto Nazionale dei Tumori and the private Istituto Europeo di Oncologia, both located in Milan), the National Neurological Institute Carlo Besta in Milan, the private scientific entity TERA Foundation in Novara. In addition, the Ministry of Health has one representative in the Board, such as the Institutional Participants (the City of Pavia, the Universities of Milan and Pavia, the Politecnico di Milano, the Institute of Nuclear Physics INFN) and the Participants (two bank foundations, Cariplo and Banca del Monte di Lombardia).

CNAO is one of the six centers globally and the four in Europe that treats tumors with carbon ions and protons. There are now three treatment rooms with four beam ports—three horizontal and one vertical—as well as one room set aside for experiments. The core of CNAO is a synchrotron that can generate 400 MeV/u of energy for carbon ions, or a maximum beam range of 27 cm in water, and 250 MeV of energy for protons, or 38 cm in water. The main features of CNAO technology are described in [6] and a view of the facility and a picture of the synchrotron are shown in Fig. 2.

Fig. 2
figure 2

Left: at the front, the Centre for Oncological Hadron Therapy (CNAO) hospital building; at the back, the power station and the roof of the synchrotron vault. Right: a view of the synchrotron and of the beam transport lines

Full size image

An expansion project is presently underway to add new technologies, among which a new accelerator devoted to Boron Neutron Capture Therapy (BNCT), a clinical research option for the treatment of diffuse tumours. The purpose of this contribution is to describe CNAO main features and activities, so as to answer the question: “Is CNAO the right place for experiments with BNCT ?”.

2 Clinical activities at CNAO

Patient treatments started in 2011 and both protons and carbon ions particles are routinely delivered in three treatment rooms. CNAO’s clinical history concerns about 5,000 patients treated, almost equally divided between the two types of particles. The treatments mainly concern a dozen tumour pathologies, which are recognized by the National Health System: chordomas and chondrosarcomas of the base of the skull and spine, tumours of the brainstem and spinal cord, sarcomas of the cervical-cephalic, para-spinal, retroperitoneal and pelvic districts, sarcomas of the extremities resistant to traditional radiotherapy (osteosarcomas, chondrosarcomas), intracranial meningiomas in critical locations (close proximity to the optic pathways and brainstem), orbital and periorbital tumours (e.g. paranasal sinuses), including ocular melanoma, adenoid cystic carcinoma of the salivary glands, paediatric solid tumours. In addition, experimental clinical studies are underway to extend the application to other radio-resistant diseases, such as pancreatic, liver and high-risk prostate cancers, recurrences of rectal cancers, gynaecological cancers.

Patients' data suggest that around 20% were treated at CNAO in a re-irradiation environment, and more than 10% of patients have significant tumour volumes (> 500 cc); yet, the local control looks promising and compatible with literature statistics for similar hadron therapy treatments. The locoregional toxicities, which are consistently rated using Common Toxicity Criteria Adverse Events (CTCAE), are minimal and, in some cases, better than reported in the literature, due to the active scanning system's performance and meticulous treatment planning. It is not the purpose of this text to present the clinical results related to the single pathologies, but a summary of the most common diseases treated with hadrons is outlined in [5] and references are reported therein. An extensive documentation concerning CNAO activities and results has been published in scientific journals by CNAO researchers: covering the last three years, 107 papers in 2021, 86 in 2022 and more than 60 in the first 10 months of 2023.

3 Research activities at CNAO

A fourth room, with a horizontal beamline, is available at CNAO for research activities. During 2023 more than 400 h of beam time have been devoted to external users, mainly from research institutes, but also from industries. Some research projects are mentioned in what follows.

The availability of multiple ions for treatment purposes is an important feature [7] and the clinical use of Helium is particularly promising. In fact, when multiple ions are used, it is possible to increase the energy deposition per unit track length (named LET—Linear Energy Transfer) in the target region, while maintaining low toxicity in normal tissues. Calculation systems have been developed to assess the impact of dose-averaged LET distributions on treatment outcomes [8]. Recent data also reveal even more significant biological effects of light-ion therapy, including reduced angiogenesis [9], reduced metastasis [10], and increased immune response [11].

Although CIRT (Carbon Ion Radio Therapy) provides excellent local control in the majority of cancers, it may need to be supplemented with systemic therapy in some situations to control metastasis and enhance survival. Nonetheless, relatively few radiobiology studies have looked particularly at the possible synergistic interactions between chemotherapeutic agents/radiosensitizers and CIRT. Immunotherapy is being used to treat a variety of advanced malignancies. One of the most commonly questioned topics in clinical radiobiology of carbon ions is the combination of CIRT with immunotherapy and if it can lead to better clinical results than standard therapies [12].

All multiparticle facilities worldwide employ fixed beamlines, which might be oblique, vertical, or horizontal. Carbon-ion gantries are only used for patient treatment at Heidelberg (HIT) in Germany, HIMAC and Yamagata University in Japan. It appears worthwhile to devote resources to the study and creation of a new gantry for CIRT because of the features of the current gantries [13, 14]. Less than 100 tons would be the optimal gantry weight, and it should use significantly less energy and have a low capital cost, making its purchase attractive to all carbon-ion plants. CNAO is teaming with CERN, INFN and MedAustron to design and prototype a new and performing gantry system for light ions.

The intrinsic precision of hadron therapy can be a double-edged sword, as particle range is not very well known. This directly relates to the lack of knowledge of patient morphology [15]. Due to uncertainties about range, safety margins are factored into treatment planning, which limits the full exploitation of hadron therapy. Thus, efforts have been made to develop instruments aiming at reaching precision within a few mms or, more importantly, at verifying the particle range in-vivo [16]. One example is represented by the INSIDE project—Innovative Solutions for DosimEtry in hadron therapy [17]. It is made up of a cutting-edge bi-modal system that can collect data when a patient is being exposed to radiation. It consists of a charged-particle tracker (dubbed Dose Profiler) and an in-beam PET scanner. The shape of the two detectors has been optimized to fit the CNAO treatment room, and they are combined into a movable structure. Refs. [18,19,20,21] provide a summary of the patient data acquired with the in-beam PET scanner and demonstrate the device's capacity to identify inter-fractional morphological alterations.

Studies utilizing artificial intelligence and microstructural models that identify macroscopic, microscopic, and radiobiological information in conjunction with patient-specific multi-parametric imaging and sophisticated mathematical models are becoming increasingly significant. Enhancing patient stratification, treatment response prediction, and hadron therapy customization and optimization are the main objectives of these investigations. One instance relates to patients receiving CIRT treatment at CNAO who have basal-cranial chordomas and are using radiomics and dosiomics [22].

4 Educational and training activities at CNAO

Educational and training activities have characterized the life of CNAO since the beginning: many students completed their master and doctoral thesis in Pavia; master courses and webinars have been organized and are still ongoing; many employees of CNAO give lectures and seminars in collaboration with universities and schools dealing with different hadrontherapy subjects.

In 2022 CNAO launched, in collaboration with the IUSS University Institute of Pavia, a PhD course devoted to master degrees in the biomedical field (medical doctors, radiotherapists, health physicists, biologists, biotechnologists), in the technological field (physicists, engineers, data scientists) and in humanities and social areas (law, economy, philosophy, etc.). The name of the PhD course is “The Hadron Academy” and focusses on risks and complexities in high-technology and medical innovation.

Figure 3 shows the areas of interest covered by lessons, seminars and laboratories organized within the PhD programme.

Fig. 3
figure 3

Subjects covered by the PhD programme

Full size image

The PhD program covers a minimum of 3 years with a full-time commitment. The educational path consists in both defining and carrying out a research project through advanced training activities and individual in-depth analysis. The first two cycles of 3 years (2022-2024 and 2023-2025) are presently followed by 5 students each, who won international fellowships. The new cycle is going to start in Spring 2024 and possibly the number of international fellowships will be increased.

5 Networking and collaborations

It is essential to establish networks between hadron treatment centers and traditional medical facilities, research clinics, academic institutions, and research centers. These networks may ensure the development of cultural knowledge in hadron treatment on the one hand, facilitate patient recruitment on the other, and, last but not least, provide the skills required for R&D initiatives. A multidisciplinary platform that aimed at a coordinated effort towards ion beam research in Europe has been the European Network for Light Ion Hadron Therapy (ENLIGHT), which had its inaugural meeting at the European Organization for Nuclear Research (CERN) in February 2002, and today has more than 600 participants from nearly 25 European countries (website cern.ch/enlight).

The ENLIGHT network has been instrumental in bringing together different European centres to promote hadron therapy and to help establish international discussions comparing the respective advantages of intensity modulated radiation proton and carbon therapies. A major success of ENLIGHT has been the creation of a multidisciplinary platform bringing together communities that were traditionally separated, so that clinicians, physicists, biologists, and engineers work side-by-side. Special attention is also given to the training of young researchers and professionals of oncologic radiotherapy.

CNAO is presently involved in regional (ROL – Rete Oncologica Lombarda), national (ACC – Alleanza Contro il Cancro) and international (EURACAN, JANE, EPTN, STARTER …) networks. CNAO is also coordinating the HITRIplus consortium, set up in April 2021 to establish a sustainable ion beam therapy community that joins medical, academic and industrial partners to carry out outstanding collaborative research activities to improve radio-oncology treatments for European cancer patients. The consortium has received funding from the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 101008548 (HITRIplus). In the context of advanced personalized cancer medicine, the larger goal of HITRIplus is to arm radiation oncologists with the knowledge and resources necessary to offer a state-of-the-art substitute for treating the portion of tumors that cannot be cured by protons or X-rays, or that respond better to ion beam treatment in terms of survival or recurrence rate. It specifically attempts to lower the cost and size of the particle accelerator needed to accelerate the ions to the therapeutic energy and to facilitate a greater number of patients' access to this treatment modality. The Transnational Access, a key pillar of the project, integrates and opens to external researchers and clinicians the experimental and clinical research programmes of the four European therapy facilities and of the most advanced European centre for research with heavy ions. Its Networks structure and foster research on heavy ion therapy, including both clinical and pre-clinical research. Its Joint Research Activities is developing accelerator and beam delivery technologies to extend the reach of the present generation of European ion therapy centres in terms of experimental programme and therapy techniques and studying a new design at lower cost and dimensions to make cancer ion therapy more accessible. The project will last until September 2025 and brings together 23 institutes from 14 different European countries, including for the first time the four European heavy ion radiotherapy centres.

6 CNAO expansion project

In 2018, the CNAO Foundation presented to the Italian Health Ministry an expansion project, based on a preliminary design conceived by TERA Foundation. The approval and financing of the project launched the new era of CNAO, with the addition of three new technologies to improve the treatment and research capabilities:

  • a third ion source to produce novel ion species from Helium to Iron;

  • a single room for protontherapy with a dedicated accelerator and a gantry;

  • a BNCT facility with an electrostatic accelerator and research and treatment rooms.

The new buildings are shown in colours in Fig. 4. The realization phase is underway and will be completed by the middle of 2024. It will be followed by installation and commissioning of the new technologies with the goal of starting patient treatments with the proton gantry by middle 2025 and beginning dosimetry and radiobiology tests on BNCT during the same year.

Fig. 4
figure 4

Model of the new buildings (in colours) in construction at CNAO

Full size image

The third ion source was completed and installed in fall 2022, in collaboration with INFN and an SME (Small-Medium Enterprise). The new ion species include helium ions, lithium, boron, oxygen, neon, argon and also iron, useful for bio-spatial research.

One constraint that CNAO initially chose to accept is the current lack of a proton gantry. Recent advancements in technology have madeinnovative, portable, and reasonably priced ways to obtain rotating proton beams available. On the one hand, the gantry shortens the time needed for patient placement, and on the other, it increases the number of treatment alternatives available. In addition to providing independent productivity in terms of patient throughput, the installation of a proton accelerator feeding the new gantry serves as a fallback option for patient treatments in the event that the current synchrotron requires repair or experiences downtime.

To be effective, BNCT must use a multidisciplinary approach. This approach entails physicists and engineers designing and implementing the technology required to produce and exploit neutron beams with efficacy and safety; chemists and biologists studying and optimizing boron bio-distribution and analyzing radiobiological effects; and medical physicists and physicians performing dosimetry, treatment planning, and patient care. Thus, a network of collaborations is mandatory and the nucleus has been established through a Collaboration Agreement signed in 2022 by CNAO, INFN, University of Pavia and Politecnico di Milano. This Agreement is the starting point of a larger network that will link the project to national and international groups.

CNAO has recently published a “White Book” [23] conceived to outline the status and the R&D issues dealing with the following areas of the BNCT@CNAO Project: technology and infrastructure, experimental and environmental dosimetry, development of new borated compounds, boron measurement and clinical dose verification, computational dosimetry and treatment planning, radiobiology, clinical trial procedures, medical device and drug regulatory aspects.

7 Conclusions

The Italian Ministry of Health and the Lombardy Region have sponsored the Centre for Oncological Hadron Therapy (CNAO) as a center of excellence. Approximately 5000 patients have been treated, and several research projects are underway to enhance treatment outcomes. New modalities will be added in the near future, including a new single room for proton treatment with a gantry, a third ion source to generate novel ion species, and a new accelerator for Boron Neutron Capture treatment (BNCT).

With an average age of just 40 years, a high level of education (79% university graduates, 39% with specializations and/or doctorates), and a notable degree of specialization (about 20 different organizational positions, held by people with a dozen different disciplinary backgrounds), the staff of CNAO is a fundamentally significant asset. Educational and training programmes are of paramount importance to guarantee continuity and diffusion of the ‘hadron culture’ within the healthcare system.

The CNAO Foundation is certified ISO 9001, ISO 13485 and ISO 45001 and qualified as medical device producer according to MDR 2017/745. CNAO is also accredited by Joint Commission International. Consolidated procedures and expertise are essential to guarantee safe and efficient introduction of new technologies in clinical practice.

The success of CNAO, and the positive answer to the question reported at the end of the Introduction, relies on active collaborations with many institutions and participation to clinical and research networks. They are fundamental to create the virtuous environment to foster the successful introduction of new modalities, like BNCT, and to streamline the passage of research results to patient care.