proton therapy proton therapy in medicine, proton therapy, or proton radiotherapy, is a type of particle therapy that uses a beam of protons to irradiate diseased tissue, most often to treat cancer. the chief advantage of proton therapy over other types of external beam radiotherapy is that the dose of protons is deposited over a narrow range of depth; hence in minimal entry, exit, or scattered radiation dose to healthy nearby tissues. proton therapyproton therapy equipment at the mayo clinic in rochester, minnesotaother namesproton beam therapyicd-10-pcsz92.3 when evaluating whether to treat a tumor with photon or proton therapy, physicians may choose proton therapy if it is important to deliver a higher radiation dose to targeted tissues while significantly decreasing radiation to nearby organs at risk. the american society for radiation oncology model policy for proton beam therapy says proton therapy is considered reasonable if sparing the surrounding normal tissue "cannot be adequately achieved with photon-based radiotherapy" and can benefit the patient. like photon radiation therapy, proton therapy is often used in conjunction with surgery and/or chemotherapy to most effectively treat cancer. description main article: radiation therapy § mechanism of action in a typical treatment plan for proton therapy, the spread out bragg peak (sobp, dashed blue line) shows how the radiation is distributed. the sobp is the sum of several individual bragg peaks (thin blue lines) at staggered depths. note that the vast majority of the proton radiation is delivered to the tumor, not to the skin and shallow tissues in front of the tumor or to the deep tissues behind the tumor. the red line shows the depth-dose plot of an x-ray beam (photon or conventional radiation therapy) for comparison. the pink area represents additional doses of x-ray radiotherapy in front and behind the tumor – which can damage normal tissues and cause secondary cancers, especially of the skin. 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 and thus eliminating the tumor. cancerous cells are particularly vulnerable to attacks on dna because of their high rate of division and their limited ability to repair dna damage. some cancers with specific defects in dna repair may be more sensitive to proton radiation. proton therapy lets physicians deliver a highly conformal beam, i.e. delivering radiation that conforms to the shape and depth of the tumor and sparing much of the surrounding, normal tissue. for example, when comparing proton therapy to the most advanced types of photon therapy—intensity-modulated radiotherapy (imrt) and volumetric modulated arc therapy (vmat)—proton therapy can give similar or higher radiation doses to the tumor with a 50%-60% lower total body radiation dose. protons can focus energy delivery to fit the tumor shape, delivering only low-dose radiation to surrounding tissue. as a result, the patient has fewer side effects. all protons of a given energy have a certain penetration range; very few protons penetrate beyond that distance. also, 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 called the sobp (see visual). to treat tumors at greater depth, one needs a beam with higher energy, typically given in ev (electron volts). accelerators used for proton therapy typically produce protons with energies of 70 to 250 mev. adjusting proton energy during the treatment maximizes the cell damage within the tumor. tissue closer to the surface of the body than the tumor gets less radiation, and thus less damage. tissues deeper in the body get very few protons, so the dose 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 get almost no radiation, the tissues in front of (shallower than) the tumor get radiation dosage based on the sobp. equipment most installed proton therapy systems use isochronous cyclotrons. cyclotrons are considered simple to operate, reliable and can be made compact, especially with 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. modern proton systems incorporate high-quality imaging for daily assessment of tumor contours, treatment planning software illustrating 3d dose distributions, and various system configurations, e.g. multiple treatment rooms connected to one accelerator. partly because of these advances in technology, and partly because of the continually increasing amount of proton clinical data, the number of hospitals offering proton therapy continues to grow. flash radiotherapy is a technique under development for photon and proton treatments, using very high dose rates (necessitating large beam currents). if applied clinically, it could shorten treatment time to just one to three 1-second sessions, and further reducing side effects. history the first suggestion that energetic protons could be an effective treatment 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 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. in the ussr a therapeutic proton beam with energies up to 200 mev was obtained at the synchrocyclotron of jinr in dubna in 1967. the itep center in moscow, russia, which began treating patients in 1969, is the oldest proton center still in operation. the paul scherrer institute in switzerland was the world's first proton center to treat eye tumors beginning in 1984. in addition, they invented pencil beam scanning in 1996, which is now the state-of-the art form of proton therapy. the world's first hospital-based proton therapy center was a low energy cyclotron centre for eye tumors at 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 in 2001 and 2002. at the beginning of 2023, there were 41 proton therapy centers in the united states, and a total of 89 worldwide. as of 2020, five manufacturers make proton therapy systems: hitachi, ion beam applications, mevion medical systems, protom international and varian medical systems. types the newest form of proton therapy, pencil beam scanning, gives therapy by sweeping a proton beam laterally over the target so that it gives the required dose while closely conforming to shape of the targeted tumor. before the use of pencil beam scanning, oncologists used a scattering method to direct a wide beam toward the tumor. passive scattering beam delivery the first commercially available proton delivery systems used a scattering process, or passive scattering, to deliver the therapy. with scattering proton therapy the proton beam is spread out by scattering devices, and the beam is then shaped by putting items such as collimators and compensators in the path of the protons. the collimators were custom made for the patient with milling machines. passive scattering gives homogeneous dose along the target volume. therefore, passive scattering gives more limited control over dose distributions proximal to target. over time many scattering therapy systems have been upgraded to deliver pencil beam scanning. because scattering therapy was the first type of proton therapy available, most clinical data available on proton therapy—especially long-term data as of 2020—were acquired via scattering technology. pencil beam scanning beam delivery a newer and more flexible delivery method is pencil beam scanning, using a beam that sweeps laterally over the target so that it delivers the needed dose while closely conforming to the tumor's shape. this conformal delivery is achieved by shaping the dose through magnetic scanning of thin beamlets of protons without needing apertures and compensators. multiple beams are delivered from different directions, and magnets in the treatment nozzle steer the proton beam to conform to the target volume layer as the dose is painted layer by layer. this type of scanning delivery provides greater flexibility and control, letting the proton dose conform more precisely to the shape of the tumor. delivery of protons via pencil beam scanning, in use since 1996 at the paul scherrer institute, allows for the most precise type of proton delivery: intensity-modulated proton therapy (impt). impt is to proton therapy what imrt is to conventional photon therapy—treatment that more closely conforms to the tumor while avoiding surrounding structures. virtually all new proton systems now provide pencil beam scanning exclusively. a study led by memorial sloan kettering cancer center suggests that impt can improve local control when compared to passive scattering for patients with nasal cavity and paranasal sinus malignancies. application it was estimated that by the end of 2019, a total of ~200,000 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. dose escalation has sometimes shown a higher probability of "cure" (i.e. local control) than conventional radiotherapy. these include, among others, uveal melanoma (ocular tumor), skull base and paraspinal tumor (chondrosarcoma and chordoma), and unresectable sarcoma. in all these cases proton therapy gives significant improvement in the probability of local control, over conventional radiotherapy. for eye tumors, proton therapy also has high rates of maintaining the natural eye. treatment 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 increased probability of curing the disease. instead, emphasis is on reducing the dose to normal tissue, thus reducing unwanted effects. two prominent examples are pediatric neoplasms (such as medulloblastoma) and prostate cancer. pediatric irreversible long-term side effects of conventional radiation therapy for pediatric cancers are 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 minimal exit dose when using proton radiation therapy, 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, hence a reduction of acute thoracic, gastrointestinal and bladder side effects. eye tumor proton therapy for eye tumors is a special case since this treatment requires only relatively low energy protons (~70 mev). owing to this low energy, some particle therapy centers only treat eye 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. for ocular tumors, selecting the type of radiotherapy depends on tumor location and extent, tumor radioresistance (calculating the dose needed to eliminate the tumor), and the therapy's potential toxic side effects on nearby critical structures. for example, proton therapy is an option for retinoblastoma and intraocular melanoma. the advantage of a proton beam is that it has the potential to effectively treat the tumor while sparing sensitive structures of the eye. given its effectiveness, proton therapy has been described as the "gold standard" treatment for ocular melanoma. base of skull cancer when receiving radiation for skull base tumors, side effects of