Proton therapy, or proton beam therapy, is a medical procedure, 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 and there is minimal exit dose.
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 or 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.
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 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 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 or electron volts. Proton therapy treats tumors closer to the surface of the body with lower energy protons. 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 to the right. The total radiation dosage of the protons is called the spread-out Bragg peak (SOBP), shown as a heavy dashed blue line in figure to the right. 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 or shallower than the tumor receive radiation dosage based on the SOBP.
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.
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.
The second broad class are those 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.
Two prominent examples are pediatric neoplasms (such as medulloblastoma) and prostate cancer. In the case of pediatric treatments, a 2004 review gave theoretical advantages but did not report any clinical benefits.
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, and another that prostate motion is between 5–10 mm.
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%.
Overall worldwide numbers are hard to compile, but one example in the literature shows that in 2003 roughly 26% of proton therapy treatments worldwide were for prostate cancer. 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.
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. Proton therapy is far more expensive than conventional therapy. As of 2012 proton therapy required a very large capital investment (from US$100M to more than $180M).
Preliminary results from a 2009 study, including high-dose treatments, showed very few side effects.
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 (e.g. cutaneous melanoma), in some instances radiation is superior (e.g., skull base chondrosarcoma), and in some instances they are comparable (e.g., 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. Goitein & Jermann's analysis had previously determined the relative cost of proton therapy is approximately 2.4 times that of X-ray therapies. However, newer, more compact proton beam sources can be four to five times cheaper and offer more accurate three-dimensional targeting. Thus the cost is expected to reduce as better proton technology becomes more widely available. A similar analysis by Lievens & Van den Bogaert determined that the cost of proton therapy is not unrealistic and should not be the reason for denying patients access to this technology. In some clinical situations, proton beam therapy is clearly superior to the alternatives. Another study in 2007 expressed concerns about the effectiveness of proton therapy for treating prostate cancer. Although, with the advent of new developments in proton beam 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, has been quoted as saying that "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 now being installed at various sites may change this picture significantly.
As of January 2016, there are over 45 particle therapy facilities worldwide. This represents a total of more than 121 treatment rooms available to patients. More than 96,537 patients had been treated.
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|
|University of California, Davis, Crocker Nuclear Laboratory||Davis, CA||1994||Ocular treatments only (low energy accelerator)|
|Loma Linda University Medical Center||Loma Linda, CA||1990||First hospital-based facility in USA It uses the Spread Out Bragg's Peak (SOBP) shown in the above illustration.|
|Francis H. Burr Proton Center (formerly NPTC) at Massachusetts General Hospital (MGH)||Boston, MA||2001||Continuation of Harvard Cyclotron Laboratory/MGH treatment program that began in 1961|
|SCCA Proton Therapy Center at Seattle Cancer Care Alliance||Seattle, WA||2001||Part of Fred Hutchinson Cancer Research Center|
|Indiana University Health Proton Therapy Center||Bloomington, IN||2004||Formerly MPRI (Closed 4December 2014)|
|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.|
|University of Texas MD Anderson Cancer Center||Houston, TX||2006|
|ProCure Proton Therapy Center of Oklahoma||Oklahoma City, OK||2009||First of a number of planned ProCure facilities|
|CDH Proton Center||Warrenville, IL||2010||Second of a number of planned ProCure facilities|
|Roberts Proton Therapy Center, University of Pennsylvania Health System||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, is also part of a medical complex that includes the Hospital of the University of Pennsylvania, the Perelman Center for Advanced Medicine, and the Children's Hospital of Philadelphia.|
|Hampton University Proton Therapy Institute||Hampton, VA||2010|
|ProCure Proton Therapy Center||Somerset, NJ||2012||Third of a number of planned ProCure facilities|
|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|
|Scripps Health Scripps Proton Therapy Center ||San Diego, CA||2014||(5 suites, all using pencil-beam scanning precision also called IMPT) 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, Robert Wood Johnson University Hospital||New Brunswick, NJ||2015||The Laurie Proton Therapy Center is home to the world’s third MEVION S250 Proton Therapy System.|
|Texas Center for Proton Therapy||Dallas Fort Worth, Texas||2015||TCPT is a joint venture between Baylor, McKesson, and Texas Oncology. It has three pencil beam rooms and cone beam CT imaging.|
|Mayo Clinic Cancer Center||Phoenix, Arizona||2016||4 treatment rooms, Mayo Clinic Cancer Center Officially opened its doors in February 2016.|
|Mayo Clinic Jacobson Building||Rochester, MN||2016||4 treatment rooms, , officially opened its doors in May 2015.|
|The Marjorie and Leonard Williams Center for Proton Therapy||Orlando, Florida||2016||http://www.ufhealthcancerorlando.com/centers/proton-therapy-center Opened its doors in April 2016.|
|Collaborative Effort: University of Cincinnati Cancer Institute; Cincinnati Childrens Hospital Medical Center||Liberty Township, Ohio||2016||http://uchealth.com/cancer/centers-programs/proton-therapy/
MFG: Varian Medical Systems, Operational As Of Sept 2016
|Maryland Proton Treatment Center||Baltimore, MD||2016||5 treatment rooms, all using pencil-beam scanning. Maryland Proton Treatment Center is affiliated with the University of Maryland Greenebaum Comprehensive Cancer Center.|
|The Baptist Health of South Florida Miami Cancer Institute (coming soon)||Miami, Florida||2017||https://baptisthealth.net/en/health-services/cancer-services/pages/proton-therapy.aspx|
Outside the USA
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 Hospital 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.
In January 2015, it was announced the UK would get its first high energy proton beam therapy centre a year earlier than expected. A company named Advanced Oncotherapy signed a deal with Howard de Walden Estate to install a machine in Harley Street, the heart of private medicine in London, to be ready by 2017. The company promises that its use of a linear accelerator allows for facilities one-third smaller and one-fifth the cost of facilities based on existing cyclotron designs. The NHS has been criticised by some doctors for buying "old" equipment.
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