the radiation can include pituitary hormone dysfunction and visual field deficit—after radiation for pituitary tumors—as well as cranial neuropathy (nerve damage), radiation-induced osteosarcoma (bone cancer), and osteoradionecrosis, which occurs when radiation causes part of the bone in the jaw or skull base to die. proton therapy has been very effective for people with base of skull tumors. unlike conventional photon radiation, protons do not penetrate beyond the tumor. proton therapy lowers the risk of treatment-related side effects from when healthy tissue gets radiation. clinical studies have found proton therapy to be effective for skull base tumors. head and neck tumor proton particles do not deposit exit dose, so proton therapy can spare normal tissues far from the tumor. this is particularly useful for head and neck tumors because of the anatomic constraints found 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, hence a minimal acute toxicity profile, even in patients who got multiple prior courses of radiotherapy. left-side breast cancer when breast cancer — especially in the left breast — is treated with conventional radiation, the lung and heart, which are near the left breast, are particularly susceptible to photon radiation damage. such damage can eventually cause lung problems (e.g. lung cancer) or various heart problems. depending on location of the tumor, damage can also occur to the esophagus, or to the chest wall (which can potentially lead to leukemia). one recent study showed that proton therapy has low toxicity to nearby healthy tissues and similar rates of disease control compared with conventional radiation. other researchers found that proton pencil beam scanning techniques can reduce both the mean heart dose and the internal mammary node dose to essentially zero. small studies have found that, compared to conventional photon radiation, proton therapy delivers minimal toxic dose to healthy tissues and specifically decreased dose to the heart and lung. large-scale trials are underway to examine other potential benefits of proton therapy to treat breast cancer. lymphoma though chemotherapy is the main treatment for 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 expectancy following therapy. prostate cancer 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). 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 most of their treatment slots to prostate treatments. for example, two hospital facilities devote ~65% and 50% of their proton treatment capacity to prostate cancer, while a third devotes only 7.1%. worldwide numbers are hard to compile, but one example says that in 2003 ~26% of proton therapy treatments worldwide were for prostate cancer. gastrointestinal malignancy a growing amount of data shows that proton therapy has great potential to increase therapeutic tolerance for patients with gi malignancy. the possibility of decreasing radiation dose to organs at risk may also help facilitate chemotherapy dose escalation or allow new chemotherapy combinations. proton therapy will play a decisive role for 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. hepatocellular carcinoma post-treatment liver decompensation, and subsequent liver failure, is a risk with radiotherapy for hepatocellular carcinoma, the most common type of primary liver cancer. research shows that proton therapy gives favorable results related to local tumor control, progression-free survival, and overall survival. other studies, which examine proton therapy compared with conventional photon therapy, show that proton therapy gives improved survival and/or fewer side effects; hence proton therapy could significantly improve clinical outcomes for some patients with liver cancer. reirradiation for recurrent cancer for patients who get local or regional recurrences after their initial radiation therapy, physicians are limited in their treatment options due to their reluctance to give additional photon radiation therapy to tissues that have already been irradiated. re-irradiation is a potentially curative treatment option for patients with locally recurrent head and neck cancer. in particular, pencil beam scanning may be ideally suited for reirradiation. research shows the feasibility of using proton therapy with acceptable side effects, even in patients who have had multiple prior courses of photon radiation. comparison with other treatments a large study on comparative effectiveness of proton therapy was published by teams of the university of pennsylvania and washington university in st. louis in jama oncology, assessing if proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations and overall survival compared with concurrent photon therapy and chemoradiotherapy. the study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent and concluded, "proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival". a significant number of randomized controlled trials is currently recruiting, but only a limited number have been completed as of august 2020. a phase iii randomized controlled trial of proton beam therapy versus radiofrequency ablation (rfa) for recurrent hepatocellular carcinoma organized by the national cancer center in korea showed better 2-year local progression-free survival for the proton arm and concluded that proton beam therapy (pbt) is "not inferior to rfa in terms of local progression-free survival and safety, denoting that either rfa or pbt can be applied to recurrent small hcc patients". a phase iib randomized controlled trial of proton beam therapy versus imrt for locally advanced esophageal cancer organized by university of texas md anderson cancer center concluded that proton beam therapy reduced the risk and severity of adverse events compared with imrt while maintaining similar progression free survival. another phase ii randomized controlled trial comparing photons versus protons for glioblastoma concluded that patients at risk of severe lymphopenia could benefit from proton therapy. a team from stanford university assessed the risk of secondary cancer after primary cancer treatment with external beam radiation using data from the national cancer database for 9 tumor types: head and neck, gastrointestinal, gynecologic, lymphoma, lung, prostate, breast, bone/soft tissue, and brain/central nervous system. the study included a total of 450,373 patients and concluded that proton therapy was associated with a lower risk of second cancer. the issue of when, whether, and how best to apply this technology is still under discussion by physicians and researchers. one recently introduced method, 'model-based selection', uses comparative treatment plans for imrt and impt in combination with normal tissue complication probability (ntcp) models to identify patients who may benefit most from proton therapy. clinical trials are underway to examine the comparative efficacy of proton therapy (vs photon radiation) for the following: pediatric cancers—by st. jude children's research hospital, samsung medical center base of skull cancer—by heidelberg university head and neck cancer—by md anderson, memorial sloan kettering and other centers brain and spinal cord cancer—by massachusetts general hospital, uppsala university and other centers, nrg oncology hepatocellular carcinoma (liver)—by nrg oncology, chang gung memorial hospital, loma linda university lung cancer—by radiation therapy oncology group (rtog), proton collaborative group (pcg), mayo clinic esophageal cancer—by nrg oncology, abramson cancer center, university of pennsylvania breast cancer—by university of pennsylvania, proton collaborative group (pcg) pancreatic cancer—by university of maryland, proton collaborative group (pcg) x-ray radiotherapy irradiation of nasopharyngeal carcinoma by photon (x-ray) therapy (left) and proton therapy (right) 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 sparing 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, needlessly harming tissue deeper in the body and damaging the skin and surface tissue opposite the beam entrance. the differences between the two methods depends on: width of the sobp depth of the tumor number of beams that treat the tumor the x-ray advantage of less harm to skin at the entrance is partially counteracted by harm to skin at 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 get no radiation. thus, x-ray therapy causes slightly less damage to 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 which became us fda approved in 2017) and varian. surgery physicians base the decision to use surgery or proton therapy (or any radiation therapy) on tumor type, stage, and location. sometimes surgery is superior (such as cutaneous melanoma), sometimes radiation is superior (such as skull base chondrosarcoma), and sometimes are comparable (for example, prostate cancer). sometimes, they are used together (e.g., rectal cancer or early stage breast cancer). the benefit of external beam proton radiation is in the dosimetric difference from external beam x-ray radiation and brachytherapy in cases where use of radiation therapy is already indicated, rather than as a direct competition with surgery. in 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 main articles: radiation therapy § side effects, and adverse effect proton therapy is a type of external beam radiotherapy, and shares risks and side effects of other forms of radiation therapy. 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,