Rapid technological progress in recent years has led to an evolution in all areas of medicine and has significantly influenced radiation oncology. Today, a new frontier in radiation therapy is represented by the hadrontherapy, which is the use of protons and atomic nuclei (ions) called hadrons (from the Greek hadrós, strong) that are subjected to a strong nuclear force.
The advantages of hadrontherapy compared to traditional radiotherapy are:
- The release of energy (and thus the destruction of cells) is done selectively, targeting only cancer cells. The damage incurred in the body on initial penetration is relatively small and significant release of energy is confined only to the vicinity where the cancer is located (a phenomenon referred to as the Bragg Peak). This maximizes the destruction of cancerous tissues while minimizing collateral effects on healthy tissues
- The beam of hadronic particles remains collimated as it penetrates the biological material. The high collimation of the beams of hadrons further minimizes damage to healthy tissues
- The energy release mechanism for hadrontherapy causes a large amount of breaks on the chemical links present in biological macromolecules, especially DNA. The latter has the ability to repair itself, but if the number of broken links is excesive it loses its function of self-reparation and the cells remain inactive and die. In conventional radiotherapy the DNA damage is modest; on the contrary, in the hadrontherapy with carbon ions the number of breaks allows the destruction even of tumors resistant to conventional therapy.
Together these three benefits result in a significant destructive effect on biological tissues, for which reason the target (tumor) must be positioned with a degree of accuracy which is much greater than that associated with conventional radiotherapy.
Effective application of hadrontherapy requires the following:
- a proton and / or ion accelerator (such as the circular accelerator or synchrotron) producing a number of particle beams
- a system for transporting the beam in the treatment room
- a procedure for precisely positioning the patient for treatment
- complete control of the energy to be released i.e. the dose
- a three-dimensional customized patient treatment system obtained by integrating diagnostic imaging results (CT, MRI, PET).
It is important to note that since hadrontherapy is a relatively recent addition to the modern oncological treatment panorama, a number of indications are still in the experimental stage.
The National Centre of Oncological Hadrontherapy (CNAO), located in Pavia, is the first Centre of Hadrontherapy in Italy provided with a beam able to irradiate patients with protons or carbon ions for the treatment of radioresistant tumors.
The Synchrotron: what it is and how it works
CNAO’s ‘High Technology’ components consist of a set of accelerators and transport lines of particle beams. The beams are generated by sources that produce carbon ions and protons. The most important accelerator machine is the Synchrotron. The synchrotron at CNAO is a prototype resulting from the research in high energy physics made possible through the collaboration of the Istituto Nazionale di Fisica Nucleare (INFN), CERN (Switzerland), GSI (Germany), LPSC (France) and of the University of Pavia University (Italy). It is based mostly on Italian technology.
The synchrotron is a “donut” 80 meters long with a diameter of 25 meters. In two areas inside the circumference the beams of particles are created in devices called “sources”, which contain plasma formed by the gas atoms that have lost their electrons. Using magnetic fields and radio frequency pulses, these atoms are extracted and the protons and carbon ions are selected. In this way “packages” composed of beams -each one containing billions of particles- are formed.
These packages are pre- accelerated and sent to the synchrotron where, initially, they travel at about 30,000 kilometers per second. Subsequently they are accelerated to kinetic energies of 250 MeV for protons and 480 MeV for carbon ions (the MeV, equivalent to one million electron volts, is the unit of energy used in nuclear and atomic scale phenomena).
The particle beam is accelerated in the synchrotron and travels about 30,000 kilometers in a half second to reach the desired energy. The beams are then sent to one of the three treatment rooms. Above this station there is a magnet of 150 tons which bends 90 degrees the particle beam and directs it from above to the person to be healed.
The beam that strikes the cells of the tumor is like a “brush” that moves in a manner similar to that of electrons in a TV and acts with a precision of 200 micrometers (two tenths of a millimeter).
This accuracy is achieved by means of:
- Constant monitoring of the patient to follow any movements of the body (breathing, for example) that can change the location of the tumor, using infrared cameras to measure movement in a three-dimensional way
- Two scanning magnets that, based on feedback of the beam monitoring system, move the “brush” along the outline of the tumor
In this way, section by section, the tumor is destroyed. The transition from one section to another deeper section is achieved by increasing the beam energy. The entire radiation lasts a few minutes.
Hadrontherapy is an advanced form of radiotherapy. Radiation therapy alone, or combined with surgery and/or chemotherapy, improves local control in different tumors. In addition, the non-invasive nature of radiation therapy represents a suitable alternative to surgery for those tumors located in anatomical locations complicated by vital organs or in sites where tumor removal would be too debilitating for the patient. Today, about 50% of patients with cancer are undergoing radiation therapy. Hadrontherapy is not a substitute for conventional radiotherapy, but arises as an ideal technique for those cancers where conventional radiotherapy does not provide significant advantages in particular for “radio-resistant” tumors and for those located close to organs at risk. “Radio-resistant” tumors are those which, because of their biological behavior, are less likely to be cured by conventional radiotherapy. Tumors located in the vicinity of organs deemed “critical” or “at risk”, often cannot be irradiated by doses high enough to be effective, because it could harm healthy organs. The possibility of cure depends not only on factors related to the tumor itself, such as its radio-sensitivity and anatomic location, but also on factors related to the radiation treatment, such as the total dose delivered and the precision of the technique employed in irradiating the site of the disease. These “limits” can be overcome by hadrons (specifically protons and carbon ions) due to their different physical nature compared to X-rays used in conventional radiotherapy. The intrinsic physical properties of these particles allow us to conform the dose “around the tumor” with greater accuracy, while saving the surrounding healthy tissue. With carbon ions in particular, one has the advantage of inducing more damage to the tumor “overcoming” its intrinsic radio-resistance.
The clinical use of these particles, especially that of carbon ions, has been limited up to now due to the limited availability of this therapy worldwide. However, initial clinical experiences have demonstrated their therapeutic advantage in many cases and the longer-term results continue to be encouraging .
Clinical trials have increased in recent years, and are aimed at expanding the indications to include other anatomical sites. Here, it should be noted that studies have shown that the results obtained with hadrontherapy are as good as or better than those obtained with conventional radiotherapy .
However, to estimate the real clinical benefits of hadrontherapy a representative number of treated patients should be carefully followed up for a long period of time. Those indications in which the advantage has been demonstrated are known as “consolidated indications”. There are other cases where there have been promising results, but on too few patients for a limited number of years for definite conclusions to be reached. Thus, while there is a substantial amount of theoretical evidence to support the efficacy of hadrontherapy in these cases, there is a need for more empirical data from larger studies over a longer period of time to confirm this evidence. These are potential indications.In any case, only after assessment of individual cases by medical specialists can one establish the best therapeutic approach and, eventually, confirm the need for hadrontherapy treatment.
Currently, scientific literature has documented the following consistent results for some cancers that have been treated for a long time with protons and carbon ions.
Chordoma and chondrosarcomahave traditionally been considered an indication for proton therapy. Their characteristic anatomical location of onset, the base of the skull and spine, the difficulties of treatment with surgery or radiotherapy and the local growing trend rather than distant metastases provide the scientific rationale for believing that an increase of local control can result in increased survival and thus justify the use of sophisticated techniques of radiotherapy. The results so far obtained and published in the literature show that radiation therapy with protons could constitute the standard treatment after surgery for these tumors. Results obtained so far indicate that radiotherapy with carbon ions is equally safe and could produce superior results over those obtained with protons. The rationale for the use of hadrontherapy in the treatment of atypical meningioma, malignant or recurrent meningioma is mainly based on its high spatial selectivity. The frequent place of occurrence of meningioma is at the base of the skull, in close proximity to structures like the optic tract and the brainstem (vital organ) makes it improbable, in most cases, for successful surgery. The presence of any residual tumor after surgery amply justifies the use of this technique.
Radiotherapy with protons for the treatment ofuveal melanomais now an established alternative to radical surgical treatment requiring enucleating the eye. Introduced in 1975, the proton therapy has gained wide acceptance in the scientific community because it has been shown that disease-free survival and overall survival results obtained with protons are similar to those obtained by enucleation. Local control with organ preservation is the most important goal of treatment with protons.
Sarcomas of the bone tissue in difficult locations such as the spine, pelvis and the skull where the presence of the spinal cord, internal organs and brain, respectively, fully justify the use of proton therapy and carbon ion therapy given the well-known radio resistance of this type of cancer. In the same way, carbon ions are the ideal tool for the treatment of retroperitoneal soft tissue sarcoma, inoperable or not radically operated, or recurrences. Salivary glands tumors are radio-resistant and the treatment of choice is surgery, usually combined with radiotherapy in cases of incomplete resection, advanced or high grade tumors. Although this therapeutic approach has improved the results in terms of local control compared with surgery alone, this is still not optimal. The radio resistance of these tumors has led to the use of neutrons due to their superior radiobiological properties suitable to overcome their radio-resistance. Unfortunately, in spite of the therapeutic success in terms of disease control, data from studies using neutrons, showed significant toxicity. Carbon ions, thanks to their intrinsic radiobiological properties that reduce tumor radio-resistance without significant side effects, have shown better results.
Radiotherapy with protons has aroused great interest for its possible use in pediatric therapy. In recent decades, thanks to the improved effectiveness of new treatment protocols, there is a significant increase in survival rates, which at the same time, allow for assessment of the extent of late side effects related to radiation treatment. Endocrine and neurosensory deficits, growth retardation, malformations and other side effects that occur close to or later after the end of the therapy have been well studied. Numerous pre-clinical dosimetry studies have revealed appreciable reduction of irradiation to healthy tissues from treatment plans carried out with protons compared to those made by X-ray Another important finding observed with the use of protons is the drastic decrease of the integral dose, i.e. the total amount of energy administered to the patient during irradiation, leading to increased risk of second cancer (carcinogenic effect). These “savings” of radiation are of substantial importance in children whose tissues, still immature, are much more susceptible to the harmful effects of radiation.
The head and neck cancersare the subject of considerable interest. The potential benefit of hadrontherapy in the treatment of these tumors derives from where they occur. They often arise at or close to the base of the skull, surrounded by healthy vital organs such as: the spinal cord, brainstem, temporal lobes of the brain, auditory and optical pathways and pituitary gland. The location close to these important organs makes it impossible for the administration of the high radiation doses necessary to eradicate the disease. Pre-clinical and clinical studies suggest a potential benefit of treating those tumors characterized by low radio sensitivity and critical location with hadrontherapy. Paranasal sinuses and adenoid cystic carcinoma, some selected tumors of the nasopharynx and bone and soft tissue sarcomas are being studied. In the case of sarcomas of the head and neck, the use of hadrontherapy is justified for those situations in which photons therapy is unable to obtain adequate dose distributions. The use of carbon ions is also reserved for cases with macroscopic disease in this location.
Do not confuse the Synchrotron with a normal Cyclotron