Proton therapy

Tissue irradiation reaches a maximum only in the last few millimeters of the particle’s flight.

Unlike fast electrons or gamma radiation (X-rays), accelerated protons transfer energy to living tissue over the last few millimeters of run. (Vertical - absorbed dose, horizontal - depth in centimeters)

Proton therapy, like other types of radiotherapy, acts by targeting accelerated ionizing particles (in this case, protons dispersed in a particle accelerator) to an irradiated tumor. These particles damage the DNA of cells, ultimately causing their death. Cancer cells, due to the high rate of their division and because of their lower ability to repair damaged DNA, are especially sensitive to the attack on the carrier of their heredity ^[1] .

Due to the relatively large mass, protons experience only a small transverse scattering in the tissue, and the scatter in their path length is very small; the beam can be focused on the tumor without causing unacceptable damage to the surrounding healthy tissue. All protons of a given energy have a very specific range; their insignificant number exceeds this distance. Moreover, almost the entire radiation dose is released into the tissue at the last millimeters of particle path; this maximum is called the Bragg peak . The location of the Bragg peak depends on the energy to which the particles were accelerated in the accelerator, this energy in most cases should be in the range from 70 to 250 million electron volts (MeV). Therefore, it becomes possible to focus the area of ​​cell destruction by a proton beam in the depths of healthy tissue surrounding the tumor; tissues located up to the Bragg peak receive some minor dose. Moreover, this dose can be further reduced due to the precision rotation of either the beam itself around the patient using a special gantry device ^[2] , or the precision rotation of the entire patient’s body with a spatially stable proton beam. Tissues located behind the Bragg peak practically do not receive an ionization dose.

The first suggestion that accelerated protons can be an effective treatment was made by Robert Wilson in an article published in 1946 ^[3] . At this time, he was involved in the design of the Harvard Cyclotron Laboratory (HCL). The first experiments on patient irradiation were done on accelerators built for physical research, namely, at the Radiation Laboratory in Berkeley in 1954 and at Uppsala University (Sweden) in 1957.

Collaboration between the HCL and the Massachusetts General Hospital (MGH) for the development of proton therapy began in 1961. The program was modernized and improved over the next 41 years, 9,116 patients were treated until the cyclotron closed in 2002.

In the USSR, a therapeutic proton beam with an energy of up to 200 MeV was obtained at the synchrocyclotron of the Joint Institute for Nuclear Research (Dubna) in 1967. The beam was brought into a specialized treatment room attached to the synchrocyclotron case, where a rotational chair was placed to fix the patient, dosimetric, adjustment and other auxiliary equipment designed to control patient exposure ^[4] .

In the USA, in 1990 a specialized clinical proton therapy center was built in Loma Linda, California (Loma Linda University Medical Center (LLUMC), recently renamed the James Slater Proton Therapy Center, James M. Slater Proton Therapy Center.

Then the Northeast Proton Therapy Center was built at the Massachusetts Central Hospital (recently renamed the Francis Barr Proton Therapy Center, Francis H. Burr Proton Therapy Center). During 2001 and 2002, all HCL therapeutic programs were moved here.

The method allows you to accurately target the tumor and destroy it at any depth of the body. The surrounding tissue takes minimal damage. For this reason, proton therapy is especially good for some types of tumors, where conventional radiation therapy does unacceptable damage to surrounding tissues. This is especially important in the treatment of children, when prolonged exposure leads to the emergence of secondary tumors that occur with excessive radiation doses. Due to the lower dose load on healthy tissues, protons produce much less side radiation effects than in conventional radiation therapy.

It seems that the logic of using proton therapy in the treatment of the most common oncological diseases (for example, a lung tumor, intracranial, in the cervical spine, etc.) is similar to the logic of surgery, as the final local therapy. However, this is not quite true. Cancer cells are able to spread in microscopic amounts from the tumor focus in the early stages of the disease.

Historically, there was an area where proton therapy had an undeniable advantage: choroidal malignant melanoma , since in this disease the only method was eye removal. Today, proton therapy can cure this tumor without injury. Proton treatment of eye tumors is carried out in Sacramento at the Davis facility of the University of California, this facility is under operational control of the Department of Radiation Oncology, University of California. It is estimated that over 44,000 patients have been treated with proton therapy with a positive outcome. Since 1984, around 5,000 patients with eye tumors have been treated at the Paul Scherer Institute in Switzerland.

Proton irradiation has made impressive progress in the treatment of many types of cancer, including brain cancer, spinal cancer, and prostate cancer. Some researchers have suggested that antiprotons may be even more effective in the fight against cancer cells. So far, however, only the very initial stage of research on cellular structures has been completed.

Proton therapy has so far used very massive and heavy equipment weighing hundreds of tons. So, for example, the synchrocyclotron of the therapeutic center in Orsay (France) has a total mass of 900 tons. Previously, such equipment was available only in physical centers for the study of elementary particles; in relation to Orsay, it was necessary to convert the machine for physical experiments into a medical one.

One of the obstacles to the widespread use of protons for cancer treatment is the size and cost of the necessary cyclotron or synchrocyclotron equipment. The Massachusetts Institute of Technology (MIT), in collaboration with a team of manufacturers, is developing a relatively compact accelerator system for irradiating patients with protons. As soon as this technology is debugged, and if the dose loads in the tissues necessary for effective therapy are achieved, a significant increase in the number of such installations is possible. So, the already mentioned hospitals in St. Louis, Missouri, and two hospitals in Florida are planning to purchase these facilities. The Oklahoma City Center plans to use IBA's cyclotron development.

To date, the Institute of Proton Therapy of the Midwest at Indiana University has earned. In the summer of 2006, two more medical centers were launched: the Commercial Proton Oncology Center named after M. D. Anderson at the University of Texas, Houston, Texas; and the Proton Therapy Institute at the University of Florida at Jacksonville, Florida. (The latter institute is unique in that it is located on the surface of the earth. In all the centers built before, the proton cyclotron was located underground to provide radiation protection. In Florida, the groundwater level is very high, so the accelerator room was raised to the surface and the wall thickness increased up to 5.5 meters in some areas for reliable radiation protection.)

The University of Pennsylvania is set to open the world's largest proton therapy institute (the Roberts Proton Therapy Center at the Perelman Center for Advanced Medicine) in 2009. The last three buildings were designed by the architectural firm Tsoi / Kobus & Partners, and proton therapy equipment was supplied by Ion Beam Applications (IBA).

In July 2007, DuPage Central Hospital (CDH) in Winfield, Illinois, announced its intention to establish a joint venture with ProCure Treatment Centers Inc. and Radiation Oncology Consultants, Ltd. in order to organize cancer treatment in Illinois. Treatment of patients with CDH is expected to begin in 2010. In a similar partnership, ProCure is building a proton therapy center in Oklahoma City, Oklahoma, with an opening scheduled for 2009-2010. Both institutions purchase equipment from IBA.

As of February 2019, according to the PTCOG (Particle Therapy Co-Operative Group), 92 proton accelerators used to treat diseases were operating in the world, including installations at research institutes. Most of them work in the USA (31), Japan (20) and Germany (8) ^[6] .

Until recently, very limited clinical trials were conducted in Russia on the basis of multifunctional irradiators of physical research centers. So, proton therapy was developed on the basis of ITEP (Moscow), Russian Science and Technology Center (based on PNPI named after B.P. Konstantinov , Gatchina, Leningrad Region), JINR (Dubna). These three centers could accept only about 1% of all those in need of this type of treatment. . As of 2018, in total, the centers of proton therapy in Russia can treat no more than 1,150 patients per year. The cost of treatment is available only for a very wealthy part of the population ^[7] .

ISRC named after A.F. Tsyba (Obninsk)

At the end of November 2015 ^[8] at the A.F. Tsyba, Obninsk , the treatment of patients at the proton therapy unit in Protvino has begun ^{[9] [10]} . At the end of March 2016, the physical launch of the Prometheus proton therapy complex ^{[11] [12] [13]} took place in Obninsk. By November 2016, doctors of the MRRC them. A.F. Tsyba treated more than 60 patients (about 2000 sessions of irradiation of head and neck tumors were performed) with a proton beam at the Prometeus complex (the first, which came into operation), located in Protvino ^{[14] [15] [16] [17] [18]} . The existing single-cabin proton complex, based on the experience already gained, can treat 400-500 people a year when operating in two shifts.

MIBS Proton Therapy Center (St. Petersburg)

In 2015, the construction of the first clinical proton therapy center in the Russian Federation with a rotary gantry system began in St. Petersburg . A private investor in the project was Sergey Berezin Medical Institute (IIBI) company ^[19] , which invested 7.5 billion rubles in the construction and equipment of the center. The project was recognized as strategic for St. Petersburg ^[20] . The center is equipped with a proton accelerator (cyclotron) manufactured by Varian Medical Systems and two treatment rooms with a rotating gantry. In the fall of 2017, the Proton Therapy Center for MIBS began receiving patients ^[21] . The planned throughput is up to 800 people per year, at least half of which are patients under the age of 18. For the first full year of operation (2018), the Proton Therapy Center for MIBS treated almost 200 people, more than 45% of whom were children ^[22] .

Dimitrovgrad Radiological Center

In January 2019, the Dimitrovgrad Radiological Center received a state license for proton therapy. The planned capacity is 1200 patients per year ^{[23] [24] [25]} . The center began receiving patients on September 20, 2019 ^{[26] [27]} .

Scientific Research

In Obninsk, at the A.F. Medical Radiological Scientific Center Tsyba is undergoing research work on methods for optimizing proton therapy ^[28] .

In Protvino, Moscow Region, the Institute of High Energy Physics is working on fundamental aspects of the treatment of radioresistant tumors using a beam of accelerated carbon ions (carbon therapy) ^[29] .

In February 2019, at the Russian Investment Forum in Sochi, the Shvabe Holding and Rusatom Helskea JSC signed an agreement on mutual understanding in the field of hadron (proton and ion) therapy projects ^[31] . At the same time, Andrei Kaprin, Director General of the NRC Research Center for Radiology, Chief Freelance Oncologist of the Russian Ministry of Health, said that Russian production of radiation units will develop in Russian oncology. As a successful example, Andrey Kaprin cited the creation of the first domestic proton accelerator, which in 2017 began work at the Medical Radiological Scientific Center named after A.F. Tsyba in Obninsk (branch of the Research Center of Radiology) ^[32] .

A new method for increasing the biological efficiency of a medical proton beam has been proposed and is being studied at JINR . The effect of inhibitors, the drugs used in the oncology clinic, on the formation of double-stranded DNA breaks in human cells under irradiation with protons at the Bragg peak was studied. The application of the proposed method, which leads to an increase in the biological efficiency of proton beams, significantly brings together the field of use of proton and carbon accelerators for therapeutic purposes ^[33] .

As of May 2017, another seven Prometeus units are being assembled in Protvino , six of which are intended for shipment abroad ^{[34] [35]} .

According to modern conservative estimates, 20% of all patients in need of radiation treatment will receive significant benefits when using proton therapy. For Russia, this means about 50 thousand patients a year. But, since so far no localizations have been defined at the level of evidence-based medicine where proton therapy would be recognized as an uncontested choice, each state, based on its financial capabilities, forms its own list of tumors in which the use of proton therapy will be paid from the budget.

- ^[36]

In Russia, there were plans to build proton therapy centers in Moscow at the hospital named after Botkin (frozen in 2013 ^[37] ), in Protvino and Pushchino (Moscow region). The proton therapy center is being reconstructed at PNPI (Gatchina, Leningrad Region) ^[38] . It is planned to commission Proton Therapy Complexes (CPT) at the Institute for Nuclear Research of the Russian Academy of Sciences in Troitsk, Moscow Region, and at the FMBA Siberian Clinical Center in Krasnoyarsk ^[39] .

In the USA, the degree of recognition of the proton therapy method is growing, its progress and potential opportunities for growth are noted. It is planned to build several new centers in the United States, most of which require investments from $ 120 million to $ 200 million:

• Hampton University in Hampton, Virginia, plans to build a $ 183 million facility with a 2010 completion date.
• The Seattle Cancer Care Alliance, scheduled to be installed in Seattle, Washington, will begin treatment in 2012.
• University of Pennsylvania, planned a large complex in Philadelphia (mentioned above), funding comes from the US Department of Defense in cooperation with the Walter Reed National Military Medical Center .
• Northern Illinois University is building a proton-based cancer and research center in Chicago based on proton therapy. Unfortunately, the equipment has not yet been certified, and this is of concern to taxpayers.
• Special Therapy Center in Oklahoma City, completed construction in 2009.
• Barnes-Jewish Hospital in Saint. Louis, Missouri.
• Broward General at Fort Lauderdale and Orlando Regional in Orlando, Florida are planning low-budget installations at around $ 20 million.
• National Taiwan University Hospital in Taipei, Taiwan received $ 400 million in donation from Foxconn to build a proton center with a scheduled completion date in 2010.
• Chang Gung Memorial Hospital in Taipei County, Taiwan, plans to complete the construction of a proton therapy center in 2010.
• In Michigan, six healthcare facilities across the state came together to form the Michigan Proton Therapy Consortium. It is planned to build a facility to service all residents of the state.

November 10, 2009 in Heidelberg (Germany) opened the Center for ion-radiation therapy - the largest medical facility in the world. The total area of ​​the center is more than 5000 m², the estimated cost is about 119 million euros.

In 2012, the Oncology Center for Proton Therapy was opened in Prague, Czech Republic, specializing in the treatment of cancer patients using the high-precision proton beam irradiation method. The center has 5 radiation therapy rooms at its disposal, including an office for treating eye tumors. More details

The following firms are currently supplying or developing proton therapy equipment:

• IBA Proton Therapy (Belgium)
• Still River Systems (USA)
• Optivus Proton Therapy (USA)
• Hitachi (Japan)
• Sumitomo Heavy Industries , (Japan)
• Varian , (USA) (acquired ACCEL (Germany) in 2007 [1] )
• Mitsubishi Electric, (Japan) [7]
• CJSC "PROTOM" (Russia)
• Particle Engineering Solutions LLC (Russia) .

1. Kostromin S.A.// Accelerators in our life. "Meeting" newspaper, Dubna. 2013-03-14
2. Klenov G.I., Khoroshkov V.S., Chernykh A.N. Accelerators for proton radiation therapy // Medical Physics: Journal. - 2013. - No. 4 . - S. 5-17 . - ISSN 1810-200X .
3. Alberto Degiovanni, Ugo Amaldi. History of hadron therapy accelerators (Eng.) // Physica Medica . - 2015. - Vol. 31. - P. 322. - DOI : 10.1016 / j.ejmp.2015.03.03.002 .
4. G.I. Klenov, V.S. Khoroshkov. Hadron radiation therapy: history, status, prospects // UFN . - 2016 .-- T. 186 . - S. 891-911 . - DOI : 10.3367 / UFNr.2016.06.0.037823 .
5. Gulidov I.A., Mardinsky Yu.S., Balakin V.E. et al. New Opportunities for Proton Therapy in Russia // Oncology Issues. - 2016. - T. 62 , No. 5 . - S. 570-572 . - ISSN 0507-3758 .
6. Thomas R. Bortfeld, Jay S. Loeffler. Three ways to make proton therapy affordable (Eng.) // Nature: Journal. - 2017 .-- 28 September ( vol. 549 , no. 7673 ). - P. 451–453 . - DOI : 10.1038 / 549451a .
7. Mardynsky Yu.S., Gulidov I.A., Gordon K.B., Gogolin D.V., Galkin V.N., Kaprin A.D., Kotukhov I.I., Lepilina O.G., Ulyanenko S .E. The first experience and early results of proton therapy with an active scanning beam at the MRNTs im. A.F. Tsyba // Research'n Practical Medicine Journal: Journal. - 2017. - April ( No. Special Edition ). - ISSN 2410-1893 .
8. Marco Durante and Harald Paganetti. Nuclear physics in particle therapy: a review (English) // Reports on Progress in Physics: journal. - 2016 .-- August 19 ( vol. 79 , no. 9 ). - DOI : 10.1088 / 0034-4885 / 79/9/096702 .
9. Elena Kokurina. Medical "submarine" // In the world of science . - 2017. - No. 8/9 . - S. 40-48 .
10.   Proton Therapy Center in Suzuoka , Japan, starting at 30
11. Manjit Dosanjh. The changing landscape of cancer therapy // CERN courier. - 2018. - January.

1. Radiation therapy with protons and heavy ions https://www.heidelberg-university-hospital.com/en/zabolevanija-i-metody-lechenija/opukholi/luchevaja-terapija-protonami-i-tjazhelymi-ionami/
2. http://www.snof.org/maladies/melanome-oculaire.html
3. Health Care Renewal: MD Anderson Cancer Center Leases Its Name
4. CERN Bulletin
5. Elsevier Article Locator
6. Microsoft PowerPoint - AAPM_Lomax.ppt Read-Only
7. “What is proton therapy?”, A. Gusev
8. “HADRON RADIATION THERAPY”, Gulidov I. A. Russia, Obninsk, Medical Radiological Scientific Center of the Russian Academy of Medical Sciences. Proceedings of the All-Russian Congress of Radiologists, Moscow, June 6 - 8, 2007, World Trade Center, p. 110-111.
9. Vladimir Sergeevich Khoroshkov
10. Proton gun in Troitsk. Video on Younube.
11. Federal State Institution “Russian Scientific Center of X-ray Radiology”
12. Official site of the Medical and Technical Complex in Dubna
13. List of Proton Therapy Centers
14. Clinical Center for Proton Therapy, MIBS (Sergei Berezin Medical Institute)