Dr. Daniel Alejandro Mazal

What is proton therapy, and what are its advantages?

Proton therapy is a highly exact and precise radiotherapy technique that makes it possible to preserve healthy tissue outside a tumoral volume, which is the target of the treatment.

Let me explain these terms in detail:

Radiotherapy is a conformal treatment technique for certain types of cancer. It is based on the use of ionizing radiations (X-rays, electrons, neutrons, protons and other types of particles). It uses accelerated beams ("external" radiotherapy) or implants of radioactive sources (brachytheray or curietherapy), generally in association with the other pillars of oncological treatment: surgery, chemotherapy, immunology... it is a local treatment that destroys cancerous cells whilst at the same time preserving healthy tissues.

By conformal radiotherapy we mean that it concentrates a "dose" of energy in the tumoral volume, with converging beams guided by images every day of the treatment (image-guided radiation therapy). Treatment can be administered in sessions, raging from seven weeks ("classic" fractionation), a few sessions ("hypo-fractionation") or single sessions, as for instance in radiosurgery treatments.

Precision consists in making the beam coincide with a white value (the tumor), with precision in a low variability between the different "shots", for instance during each session and in all the sessions.

The more traditional external radiotherapy techniques use photon beams. They are highly effective and for a long time will continue to be the referential mass treatment. It has limits, such as the fact that for every beam there is a dose of radiation that is deposited after a tumor until it goes through the patient. Fortunately, by multiplying the number of beams this effect is reduced.

When treatment involves a proton beam it is known as proton therapy, one of the most advanced techniques in the available tools for conformal radiotherapy. These particles can penetrate tissues and deposit their energy mainly on the tumor. They cause very little damage and stop after the tumor, avoiding any deep damage (figure 1).

This phenomenom is common to all charged particles: when they enter the medium they have high energy and speed, causing low ionization. They experience a gradual loss of energy and thus velocity. It is then that they can transmit their energy more deeply in the form of ionizations, which at the same time affect the DNA structure directly or indirectly. At the end they lose all their energy and stop.

But please be aware that, as with every technique, there are advantages and limitations, both of which are represented in figure 2. Fortunately, from the start of its application the advantages surpassed the limits. Many tumors are being reduced and/or kept under control with the technological advances.

In summary, the main advantage of protons is that they reduce the radiation dose in critical organs and all healthy tissues ("integral" doses) by administering radiotherapy to control a tumor. This is a great advantage in pedriatic treatments, as it reduces the sequelae and induces a long-term increase of quality of life. It also makes it possible to administer an elevated radiation dose to radioresistant tumors in certain adult patients.

What type of patients can receive it?

This question must be answered by a radiotherapy oncologist, but I will address the existing recommendation documents. In principle, all patients could benefit from a proton treatment, but it is done in stages. One of the reasons for this is its scarce availability and high cost, and the need to do a clinical test of its efficiency for each case.

There is an international consensus amongst scientific societies (including the Spanish Society of Oncological Radiotherapy - SEOR) on the localizations for which the use of protons is especially recommended. For other localizations, it is recommended to carry out comparative dosimetric and clinical studies.

Some of these recommended localizations include different types of tumors: ocular, at the base of the skull (including chordomas and chondrosarcomas), primary and metastastic tumors in the spinal cord and/or spinal column, pedriatic patients, patients with genetic symptoms with an elevated risk of toxicity and re-irradations in selected cases. All these are "rare" tumors.

The big challenge is to treat high-incidence tumors: breast, prostrate, lung, head and neck. For all these there are clinical trials and treatments in course to detect what subgroups of patients would really benefit from proton therapy; these are of course associated in a multidisclipinary sense to surgery, chemotherapy and immunology.

Quirónsalud is a pioneer in this technology. What led you to it, and when do you think it will be fully implemented in our country?

Implementing a new technology in a country is a significant challenge because of the risks involved, the level of investment, an analysis of priorities among the various lines of work, and the necessary effort from the teams implied. It is important to highlight that in the past few years Spain underwent a modernization process for its technological fleet in photon radiotherapy, and that in Europe, where there were just a few pioneer centers, one or more proton therapy facilities were installed in most countries. At the time it was ethical and appropriate to consider installing the first one in Spain.

A decision like this not only fulfills the specific need of the cases that must be treated, such as pedriatic patients, but also works as a catalyst to continue with a quality process in high-complexity treatments.

It was decided to set up a facility with one single room for proton therapy that could easily provide services to all sectors of society —public and private— with easy access and the capacity to offer all these services thanks to a partner network.

We are proud to have paved the way, since a few months after our activity another center also in Madrid started using proton therapy.

In spite of these advances, SEOR considers that Spain needs around seven treatment facilities to comply with the indications. Imminent projects have been announced, both private and public, but given their difficulty it is safe to think that growth will be progressive, and it might even take years to cover minimum needs.

The necessary initial investment to set up a proton therapy center is relevant, both regarding the incorporation of the technology and staff training, which is fundamental for the success of the project.

The costs of photon equipment may also be reduced or increased, depending on any additional complex functionalities (such as the use of nuclear resonance images with the same treatment device.)

Now that we are approaching one year of operation, and in spite of COVID-19 complications, we have been able to guarantee treatment for patients according to SEOR's recommendations.

What advances does this technology offer in comparison to more commonly implemented practices, and what can we expect for the future?

Apart from the aforementioned advances, we can confirm there is a new generation in the way radiation doses are administered with protons. All centers use small beams that "paint" a tumor point by point (sweeping the beam) and layer by layer (changing the energy). This way, the treatment is optimized regarding the specifications for therapeutic doses against the tumor and the tolerance limits of the critical organs.

At our proton therapy center we are proud to be at the world's forefront regarding complex issues, such as:

• Patient selection, using comparisons between proton and photon treatments and their respective risks.
• Calculations and measuring to treat cases with metallic implants, which are common as a way to set the column and arthrodesis after tumoral surgeries in this area. These implants are a challenge in the case of protons, as they introduce artefacts in the images and create uncertainties regarding the range. Thanks to a double-energy computed tomograph we can optimize the images in order to minimize uncertainty.
• The adaptation of the treatment plan for each patient every time there is a change in the anatomy or evolution of the tumor.

Technological advances are expected for the near future (such as for instance detecting the depth of penetration of the beam during the treatment and administering treatment while the beam rotates around the patient...) We have great expectations for the work being done for a better use of biological effects related to very short radiation times (the "FLASH" effect of healthy tissue protection), the use of mini gradiation grills also for the purpose of tissue protection and the combination of nanoparticles, which increase the effect of radiation in a differential way inside the tumor. Work is being done on synergy with different groups around the world. Finally, the great hope already being applied, but with a long path ahead, is strenghtening the effect of immunotherapy.

You studied medicine in Argentina and got your Master's and Doctor's degrees in France. You were a guest lecturer at universities in the United States and now lead the Proton Therapy Center in Madrid. Have you perceived any differences regarding the use and knowledge of medical applications of nuclear power in these countries?

I did not study medicine. First I studied engineering and then medical physics in Argentina. I did indeed pursue my career and studies further in France, USA and now Spain, with many visits to the rest of the world. There are certainly differences between countries, but there is also common ground. While all the professionals in the aforementioned countries have a high level in training, knowledge, development of academic activities, applications, regulation and development, the main differences are in resources and cultures. The resources and varying politics are obviously associated with the quantification of the installation and use of devices for prevention, diagnostics, treatment and follow-up of various pathologies. Cultures are associated to their approach to risks and benefits. In some cases this approach is more aggresive, depending on legal rather than human factors. However, the training level is increasingly open and accesible; this includes the public, patient/family associations and politicians. For this reason it is hard to see differences that are not directly related to costs and accessibility.

Do you think we are still unaware of many of the applications of nuclear power in various fields such as art, agriculture or industry?

Yes, definitely. Regarding the public, and with the exception of a select and restricted group of people motivated by science, and in spite of the increasingly accessible sources of information throughout the net, the application of nuclear technology in art and agriculture could be covered in a specialized television program at six a.m. on a Sunday morning, and people would be concerned with food sterilization! On the other hand, I believe that the public is more conscious of its application in industry, especially through the supply of electric energy from nuclear sources and the sterilization of medical products. I would never consider that everything is discovered and known. The more we know, the higher the chances of finding new nuclear applications.

We are having this interview in the midst of the pandemic. From the point of view of healthcare, what lessons can we learn from this?

Firstly, a greater awareness of the sanitary risks and their scale and of the need for all sectors to participate when a situation of alarm such as this is presented, including international cooperation.

Secondly, a more important level of sensitization of the need to invest in science and of the relationship between health policies and economic policies, regardless of the ideological orientation.

And to add a third lesson among so many others: a cultural relationship between health and society. For instance:

• The importance of social behavior and solidarity beyond any type of frontier.
• How we can modify the way we work, the way we relate to our family and the way we use technology.
• The importance of some health professions that are so unfairly forgotten.
• The fact that quality of life is a very fragile element, in spite of technological advancements, with more sensible sectors linked to factors such as age and socio-economic level.

I believe the main lesson involves social and political behavior rather than health; some examples go as far as a certain level of sacrifice for the good of the population.

Would you like to send a message related to COVID-19?

I am proud of the fact that the pandemic has not affected the activity in our center. We maintain our activity without interruptions thanks to rigorous safety and control protocols to minimize the risk of contagion in our site. In this sense, the fact that we are a monographic, highly specialized center that only caters to patients with pathologies other than COVID-19 played a significant role. We are also certified as a "COVID-19 safe hospital" and to date we have not had one single declared case.

Would you like to share some of your personal interests with our readers?

If I may interpret "interest" as something not professionally related and not as a workaholic, I could include anything from opera to rugby, and most specifically that I admire the beauty of a work of art, I deeply enjoy sunsets and I am always in awe of the complexity of the human figure. But, after a bit of thought, I believe the personal interest I would most like to share is that of travelling, to learn about different cultures and  understand the similarities and especially differences among them. This widens your mind and allows you to understand, show solidarity and also set limits to barbarity with the awareness that everyone can make a contribution to the common good.