In the field of medical procedures, proton therapy, or proton radiotherapy, is a type of particle therapy that uses a beam of protons to irradiate diseased tissue, most often in the treatment of cancer. The chief advantage of proton therapy over other types of external beam radiotherapy is that as a charged particle the dose is deposited over a narrow range of depth, and there is minimal entry, exit, or scattered radiation dose.
Proton therapy equipment at the Mayo Clinic in Rochester, Minnesota
|Other names||proton beam therapy|
Proton therapy is a type of external beam radiotherapy that uses ionizing radiation. In proton therapy, medical personnel use a particle accelerator to target a tumor with a beam of protons. These charged particles damage the DNA of cells, ultimately killing them by stopping their reproduction. Cancerous cells are particularly vulnerable to attacks on DNA because of their high rate of division and their reduced abilities to repair DNA damage. Some cancers with specific defects in DNA repair may be more sensitive to proton radiation.
Because of their relatively large mass, protons have little lateral side scatter in the tissue; the beam does not broaden much, stays focused on the tumor shape, and delivers only low-dose side effects to surrounding tissue. All protons of a given energy have a certain penetration range; very few protons penetrate beyond that distance. Furthermore, the dose delivered to tissue is maximized only over the last few millimeters of the particle's range; this maximum is called the spread out Bragg peak, often referred to as the SOBP.
To treat tumors at greater depths, the proton accelerator must produce a beam with higher energy, typically given in eV (electron volts). Accelerators used for proton therapy typically produce protons with energies in the range of 70 to 250 MeV. Adjusting proton energy during the treatment maximizes the cell damage the proton beam causes within the tumor. Tissue closer to the surface of the body than the tumor receives reduced radiation, and therefore reduced damage. Tissues deeper in the body receive very few protons, so the dosage becomes immeasurably small.
In most treatments, protons of different energies with Bragg peaks at different depths are applied to treat the entire tumor. These Bragg peaks are shown as thin blue lines in the figure in this section. It is important to understand that, while tissues behind (or deeper than) the tumor receive almost no radiation from proton therapy, the tissues in front of (shallower than) the tumor receive radiation dosage based on the SOBP.
Most installed proton therapy systems utilise isochronous cyclotrons. Cyclotrons are considered simple to operate, reliable and can be made compact, especially with the use of superconducting magnets. Synchrotrons can also be used, with the advantage of easier production at varying energies. Linear accelerators, as used for photon radiation therapy, are becoming commercially available as limitations of size and cost are resolved.
The first suggestion that energetic protons could be an effective treatment method was made by Robert R. Wilson in a paper published in 1946 while he was involved in the design of the Harvard Cyclotron Laboratory (HCL). The first treatments were performed with particle accelerators built for physics research, notably Berkeley Radiation Laboratory in 1954 and at Uppsala in Sweden in 1957. In 1961, a collaboration began between HCL and the Massachusetts General Hospital (MGH) to pursue proton therapy. Over the next 41 years, this program refined and expanded these techniques while treating 9,116 patients before the cyclotron was shut down in 2002. The world's first hospital-based proton therapy center was a low energy cyclotron centre for ocular tumours at the Clatterbridge Centre for Oncology in the UK, opened in 1989, followed in 1990 at the Loma Linda University Medical Center (LLUMC) in Loma Linda, California. Later, The Northeast Proton Therapy Center at Massachusetts General Hospital was brought online, and the HCL treatment program was transferred to it during 2001 and 2002. By 2010 these facilities were joined by an additional seven regional hospital-based proton therapy centers in the United States alone, and many more worldwide.
It was estimated that by the end of 2017, a total of ~175,000 patients had been treated with proton therapy. Physicians use protons to treat conditions in two broad categories:
- Disease sites that respond well to higher doses of radiation, i.e., dose escalation. In some instances, dose escalation has demonstrated a higher probability of "cure" (i.e., local control) than conventional radiotherapy. These include, among others, uveal melanoma (ocular tumors), skull base and paraspinal tumors (chondrosarcoma and chordoma), and unresectable sarcomas. In all these cases proton therapy achieves significant improvements in the probability of local control over conventional radiotherapy. In treatment of ocular tumors, proton therapy also has high rates of maintaining the natural eye.
- Treatments where proton therapy's increased precision reduces unwanted side effects by lessening the dose to normal tissue. In these cases, the tumor dose is the same as in conventional therapy, so there is no expectation of an increased probability of curing the disease. Instead, the emphasis is on reducing the integral dose to normal tissue, thus reducing unwanted effects.
Irreversible long-term side effects of conventional radiation therapy for pediatric cancers have been well documented and include growth disorders, neurocognitive toxicity, ototoxicity with subsequent effects on learning and language development, and renal, endocrine and gonadal dysfunctions. Radiation-induced secondary malignancy is another very serious adverse effect that has been reported. As there is no exit dose when using proton radiation therapy, the dose to surrounding normal tissues can be significantly limited, reducing the acute toxicity which positively impacts the risk for these long-term side effects. Cancers requiring craniospinal irradiation, for example, benefit from the absence of exit dose with proton therapy: dose to the heart, mediastinum, bowel, bladder and other tissues anterior to the vertebrae is eliminated, resulting in a reduction of acute thoracic, gastrointestinal and bladder side effects.
In prostate cancer cases, the issue is less clear. Some published studies found a reduction in long term rectal and genito-urinary damage when treating with protons rather than photons (meaning X-ray or gamma ray therapy). Others showed a small difference, limited to cases where the prostate is particularly close to certain anatomical structures. The relatively small improvement found may be the result of inconsistent patient set-up and internal organ movement during treatment, which offsets most of the advantage of increased precision. One source suggests that dose errors around 20% can result from motion errors of just 2.5 mm (0.098 in). and another that prostate motion is between 5–10 mm (0.20–0.39 in).
However, the number of cases of prostate cancer diagnosed each year far exceeds those of the other diseases referred to above, and this has led some, but not all, facilities to devote a majority of their treatment slots to prostate treatments. For example, two hospital facilities devote roughly 65% and 50% of their proton treatment capacity to prostate cancer, while a third devotes only 7.1%.
Proton therapy for ocular (eye) tumors is a special case since this treatment requires only comparatively low energy protons (about 70 MeV). Owing to this low energy requirement, some particle therapy centers only treat ocular tumors. Proton, or more generally, hadron therapy of tissue close to the eye affords sophisticated methods to assess the alignment of the eye that can vary significantly from other patient position verification approaches in image guided particle therapy. Position verification and correction must ensure that the radiation spares sensitive tissue like the optic nerve to preserve the patient’s vision.
Head and neck tumors
Proton particles do not deposit exit dose, which allows proton therapy to spare normal tissues distal to the tumor target. This is particularly useful for treating head and neck tumors because of the anatomic constraints encountered in nearly all cancers in this region. The dosimetric advantage unique to proton therapy translates into toxicity reduction. For recurrent head and neck cancer requiring reirradiation, proton therapy is able to maximize a focused dose of radiation to the tumor while minimizing dose to surrounding tissues which results in a minimal acute toxicity profile, even in patients who have received multiple prior courses of radiotherapy.
Lymphoma (Tumors of lymphatic tissue)
Although chemotherapy is the primary treatment for patients with lymphoma, consolidative radiation is often used in Hodgkin lymphoma and aggressive non-Hodgkin lymphoma, while definitive treatment with radiation alone is used in a small fraction of lymphoma patients. Unfortunately, treatment-related toxicities caused by chemotherapy agents and radiation exposure to healthy tissues are major concerns for lymphoma survivors. Advanced radiation therapy technologies such as proton therapy may offer significant and clinically relevant advantages such as sparing important organs at risk and decreasing the risk for late normal tissue damage while still achieving the primary goal of disease control. This is especially important for lymphoma patients who are being treated with curative intent and have long life expectancies following therapy.
An increasing amount of data reported has shown that proton therapy has great potential to increase therapeutic tolerance for patients with GI malignancies. The possibility of decreasing radiation dose to organs at risk may also help facilitate chemotherapy dose escalation or allow for new chemotherapy combinations. Proton therapy will play a decisive role in the context of ongoing intensified combined modality treatments for GI cancers. The following review presents the benefits of proton therapy in treating hepatocellular carcinoma, pancreatic cancer and esophageal cancer.
Comparison with other treatments
The issue of when, whether, and how best to apply this technology is controversial. As of 2012 there have been no controlled trials to demonstrate that proton therapy yields improved survival or other clinical outcomes (including impotence in prostate cancer) compared to other types of radiation therapy, although a five-year study of prostate cancer is underway at Massachusetts General Hospital.
NHS Choices has stated:
We cannot say with any conviction that proton beam therapy is “better” overall than radiotherapy. (...) Some overseas clinics providing proton beam therapy heavily market their services to parents who are understandably desperate to get treatment for their children. Proton beam therapy can be very costly and it is not clear whether all children treated privately abroad are treated appropriately.
The figure at the right of the page shows how beams of X-rays (IMRT; left frame) and beams of protons (right frame), of different energies, penetrate human tissue. A tumor with a sizable thickness is covered by the IMRT spread out Bragg peak (SOBP) shown as the red lined distribution in the figure. The SOBP is an overlap of several pristine Bragg peaks (blue lines) at staggered depths.
Megavoltage X-ray therapy has less "skin scarring potential" than proton therapy: X-ray radiation at the skin, and at very small depths, is lower than for proton therapy. One study estimates that passively scattered proton fields have a slightly higher entrance dose at the skin (~75%) compared to therapeutic megavoltage (MeV) photon beams (~60%). X-ray radiation dose falls off gradually, unnecessarily damaging tissue deeper in the body and damaging the skin and surface tissue opposite the beam entrance. The differences between the two methods depends on the:
- Width of the SOBP
- Depth of the tumor
- Number of beams that treat the tumor
The X-ray advantage of reduced damage to skin at the entrance is partially counteracted by damage to skin at the exit point.
Since X-ray treatments are usually done with multiple exposures from opposite sides, each section of skin is exposed to both entering and exiting X-rays. In proton therapy, skin exposure at the entrance point is higher, but tissues on the opposite side of the body to the tumor receive no radiation. Thus, X-ray therapy causes slightly less damage to the skin and surface tissues, and proton therapy causes less damage to deeper tissues in front of and beyond the target.
An important consideration in comparing these treatments is whether the equipment delivers protons via the scattering method (historically, the most common) or a spot scanning method. Spot scanning can adjust the width of the SOBP on a spot-by-spot basis, which reduces the volume of normal (healthy) tissue inside the high dose region. Also, spot scanning allows for intensity modulated proton therapy (IMPT), which determines individual spot intensities using an optimization algorithm that lets the user balance the competing goals of irradiating tumors while sparing normal tissue. Spot scanning availability depends on the machine and the institution. Spot scanning is more commonly known as pencil-beam scanning and is available on IBA, Hitachi, Mevion (known as hyperscan and not US FDA approved as of 2015) and Varian.
Physicians base the decision to use surgery or proton therapy (or any radiation therapy) on the tumor type, stage, and location. In some instances, surgery is superior (such as cutaneous melanoma), in some instances radiation is superior (such as skull base chondrosarcoma), and in some instances they are comparable (for example, prostate cancer). In some instances, they are used together (e.g., rectal cancer or early stage breast cancer). The benefit of external beam proton radiation lies in the dosimetric difference from external beam X-ray radiation and brachytherapy in cases where the use of radiation therapy is already indicated, rather than as a direct competition with surgery. However, in the case of prostate cancer, the most common indication for proton beam therapy, no clinical study directly comparing proton therapy to surgery, brachytherapy, or other treatments has shown any clinical benefit for proton beam therapy. Indeed, the largest study to date showed that IMRT compared with proton therapy was associated with less gastrointestinal morbidity.
Side effects and risks
Proton therapy is a type of external beam radiotherapy, and shares risks and side effects of other forms of radiation therapy. However the dose outside of the treatment region can be significantly less for deep-tissue tumors than X-ray therapy, because proton therapy takes full advantage of the Bragg peak. Proton therapy has been in use for over 40 years, and is a mature treatment technology. However, as with all medical knowledge, understanding of the interaction of radiation (proton, X-ray, etc.) with tumor and normal tissue is still imperfect.
Historically, proton therapy has been expensive. An analysis published in 2003 determined the relative cost of proton therapy is approximately 2.4 times that of X-ray therapies. Newer, less expensive, and dozens more proton treatment centers are driving costs down and they offer more accurate three-dimensional targeting. Higher proton dosage over fewer treatments sessions (1/3 fewer or less) is also driving costs down. Thus the cost is expected to reduce as better proton technology becomes more widely available. An analysis published in 2005 determined that the cost of proton therapy is not unrealistic and should not be the reason for denying patients access to the technology. In some clinical situations, proton beam therapy is clearly superior to the alternatives.
A study in 2007 expressed concerns about the effectiveness of proton therapy for treating prostate cancer, but with the advent of new developments in the technology, such as improved scanning techniques and more precise dose delivery ('pencil beam scanning'), this situation may change considerably. Amitabh Chandra, a health economist at Harvard University, stated, "Proton-beam therapy is like the Death Star of American medical technology... It's a metaphor for all the problems we have in American medicine.” However, another study has shown that proton therapy in fact brings cost savings. The advent of second generation, and much less expensive, proton therapy equipment which emerged by 2012 may change opinions.
As of July 2017, there are over 75 particle therapy facilities worldwide, with at least 41 others under construction. As of June 2018, there are 27 operational proton therapy centers in the United States. As of the end of 2015 more than 154,203 patients had been treated worldwide.
One hindrance to universal use of the proton in cancer treatment is the size and cost of the cyclotron or synchrotron equipment necessary. Several industrial teams are working on development of comparatively small accelerator systems to deliver the proton therapy to patients. Among the technologies being investigated are superconducting synchrocyclotrons (also known as FM Cyclotrons), ultra-compact synchrotrons, dielectric wall accelerators, and linear particle accelerators.
|Institution||Location||Year of first treatment||Comments|
|Loma Linda University Medical Center||Loma Linda, CA||1990||First hospital-based facility in USA; uses Spread Out Bragg's Peak (SOBP)|
|Crocker Nuclear Laboratory||Davis, CA||1994||Ocular treatments only (low energy accelerator); at University of California, Davis|
|Francis H. Burr Proton Center||Boston, MA||2001||At Massachusetts General Hospital and formerly known as NPTC; continuation of Harvard Cyclotron Laboratory/MGH treatment program that began in 1961; Manufactured by Ion Beam Applications|
|University of Florida Health Proton Therapy Institute-Jacksonville||Jacksonville, FL||2006||The UF Health Proton Therapy Institute is a part of a non-profit academic medical research facility. It is the first treatment center in the Southeast U.S. to offer proton therapy. Manufactured by Ion Beam Applications|
|University of Texas MD Anderson Cancer Center||Houston, TX||2006|
|ProCure Proton Therapy Center of Oklahoma||Oklahoma City, OK||2009||4 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|Northwestern Medicine Chicago Proton Center||Warrenville, IL||2010||4 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|Roberts Proton Therapy Center||Philadelphia, PA||2010||The largest proton therapy center in the world, the Roberts Proton Therapy Center, which is a part of Penn's Abramson Cancer Center, University of Pennsylvania Health System; 5 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|Hampton University Proton Therapy Institute||Hampton, VA||2010||5 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|ProCure Proton Therapy Center||Somerset, NJ||2012||4 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|SCCA Proton Therapy Center||Seattle, WA||2013||At Seattle Cancer Care Alliance; part of Fred Hutchinson Cancer Research Center; 4 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|Siteman Cancer Center||St. Louis, MO||2013||First of the new single suite, ultra-compact, superconducting synchrocyclotron, lower cost facilities to treat a patient using the Mevion Medical system's S250.|
|Provision Proton Therapy Center||Knoxville, TN||2014||3 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|California Protons Cancer Therapy Center||San Diego, CA||2014||(5 treatment rooms, manufactured by Varian Medical Systems|
|Ackerman Cancer Center||Jacksonville, FL||2015||Ackerman Cancer Center is the world's first private, physician-owned practice to provide proton therapy, in addition to conventional radiation therapy and on-site diagnostic services.|
|The Laurie Proton Therapy Center||New Brunswick, NJ||2015||The Laurie Proton Therapy Center, part of Robert Wood Johnson University Hospital, is home to the world’s third MEVION S250 Proton Therapy System.|
|Texas Center for Proton Therapy||Dallas Fort Worth, TX||2015||A collaboration by "Texas Oncology and The US Oncology Network, supported by McKesson Specialty Health, and Baylor Health Enterprises"; three pencil beam rooms and cone beam CT imaging. 3 treatment rooms, Proteus PLUS system manufactured by Ion Beam Applications|
|Mayo Clinic Cancer Center||Phoenix, AZ||2016||4 treatment rooms. Manufactured by Hitachi.|
|Mayo Clinic Jacobson Building||Rochester, MN||2015||4 treatment rooms. Manufactured by Hitachi.|
|St. Jude Red Frog Events Proton Therapy Center||Memphis, TN||2015|
|The Marjorie and Leonard Williams Center for Proton Therapy||Orlando, FL||2016||http://www.ufhealthcancerorlando.com/centers/proton-therapy-center|
|Cancer and Blood Diseases Institute||Liberty Township, OH||2016||Collaboration of University of Cincinnati Cancer Institute and Cincinnati Children's Hospital Medical Center, manufactured by Varian Medical Systems|
|Maryland Proton Treatment Center||Baltimore, MD||2016||5 treatment rooms, affiliated with the University of Maryland Greenebaum Comprehensive Cancer Center, manufactured by Varian Medical Systems.|
|Proton Therapy Center at University Hospitals Seidman Cancer Center||Cleveland, OH||2016||Only proton therapy center in Northern Ohio. One treatment room with the Mevion S250 Proton Therapy System. Part of the NCI-designated Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center is one of the nation's leading freestanding cancer hospitals.|
|Miami Cancer Institute||Miami, FL||2017||3 treatment rooms, all using pencil-beam scanning Manufactured by Ion Beam Applications|
|Beaumont Proton Therapy Center||Royal Oak, MI||2017||Single treatment room, Proteus ONE system manufactured by Ion Beam Applications|
|Emory Proton Therapy Center||Atlanta, GA||2018||Five treatment rooms, ProBeam Superconducting Cyclotron manufactured by Varian Medical Systems|
|Provision CARES Proton Therapy Center||Nashville, TN||2018||Two treatment rooms, manufactured by ProNova Solutions, LLC|
|New York Proton Center||New York, NY||2019||Four treatment rooms, manufactured by Varian Medical Systems|
|South Florida Proton Therapy Institute||Delray Beach, FL||2019||One treatment room, manufactured by Varian Medical Systems|
|UAB Proton Therapy Center||Birmingham, AL||2020 (Estimated)||One treatment room, manufactured by Varian Medical Systems|
|The University of Kansas Cancer Center||Kansas City, KS||2021 (Estimated)||Announced Feb 2019|
The Indiana University Health Proton Therapy Center in Bloomington, Indiana opened in 2004 and ceased operations in 2014.
Outside the USA
|Institution||Maximum energy (MeV)||Year of first treatment||Location|
|Paul Scherrer Institute||250||1984||Villigen, Switzerland|
|Clatterbridge Cancer Centre NHS Foundation Trust, low-energy for ocular||62||1989||Liverpool, United Kingdom|
|Centre de protonthérapie de l'Institut Curie||235||1991||Orsay, France|
|Centre Antoine Lacassagne||63||1991||Nice, France|
|Research Center for Charged Particle Therapy||350-400||1994||Chiba, Japan|
|Helmholtz-Zentrum Berlin||72||1998||Berlin, Germany|
|Proton Medical Research Center University of Tsukuba||250||2001||Tsukuba, Japan|
|Centro di adroterapia oculare||60||2002||Catania, Italy|
|Wanjie Proton Therapy Center||230||2004||Zibo, China|
|Proton Therapy Center, Korea National Cancer Center||230||2007||Seoul, Korea|
|Heidelberg Ion-Beam Therapy Center||230||2009||Heidelberg, Germany|
|Rinecker Proton Therapy Center||250||2009||Munich, Germany|
|Medipolis Proton Therapy and Research Center||235||2011||Kagoshima, Japan|
|Instytut Fizyki Jądrowej||60||2011||Kraków, Poland|
|Centro Nazionale di Adroterapia Oncologica||250||2011||Pavia, Italy|
|Proton Therapy Center, Prague||230||2012||Prague, Czech Republic|
|Westdeutsches Protonentherapiezentrum||230||2013||Essen, Germany|
|PTC Uniklinikum||230||2014||Dresden, Germany|
|Centro di Protonterapia, APSS Trento||230||2014||Trento, Italy|
|Shanghai Proton and Heavy Ion Center||230||2014||Shanghai, China|
|Centrum Cyklotronowe Bronowice||230||2015||Kraków, Poland|
|SMC Proton Therapy Center||230||2015||Seoul, Korea|
|Proton and Radiation Therapy Center, Linkou Chang Gung Memorial Hospital||230||2015||Taipei, Taiwan|
|A. Tsyb Medical Radiological Research Centre||250||2016||Obninsk, Russia|
|Clinical Proton Therapy Center Dr. Berezin Medical Institute||250||2017||Saint-Petersburg, Russia|
|Holland Proton Therapy Center||250||2018||Delft, Netherlands|
|UMC Groningen Protonen Therapie Centrum||230||2018||Groningen, Netherlands|
|The Christie||250||2018||Manchester, UK|
|Danish Centre for Particle Therapy||250||2019||Aarhus, Denmark|
|Proton Therapy Centre Apollo Hospitals||230||2019||Chennai, India|
|University College London Hospitals||250||2020||London, UK|
|Singapore Institute of Advanced Medicine||250||2020||Singapore|
In 2013 the British government announced that £250 million had been budgeted to establish two centers for advanced radiotherapy, to open in 2018 at The Christie NHS Foundation Trust in Manchester and University College London Hospitals NHS Foundation Trust. These would offer high-energy proton therapy, currently unavailable in the UK, as well as other types of advanced radiotherapy, including intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT). In 2014, only low-energy proton therapy was available in the UK, at the Clatterbridge Cancer Centre NHS Foundation Trust in Merseyside. But NHS England has paid to have suitable cases treated abroad, mostly in the US. Such cases have risen from 18 in 2008 to 122 in 2013, 99 of whom were children. The cost to the National Health Service averaged around £100,000 per case.
A company named Advanced Oncotherapy plc and its subsidiary ADAM, a spin-off from CERN, are developing a linear proton therapy accelerator to be installed among others in London. In 2015 they signed a deal with Howard de Walden Estate to install a machine in Harley Street, the heart of private medicine in London. First patient treatment at Harley Street is expected in the second half of 2020.
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