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Particle therapy
Particle therapy
Particle therapy
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Particle therapy
ICD-992.26

Particle therapy is a form of external beam radiotherapy using beams of energetic neutrons, protons, or other heavier positive ions for cancer treatment. The most common type of particle therapy as of August 2021 is proton therapy.[1]

In contrast to X-rays (photon beams) used in older radiotherapy, particle beams exhibit a Bragg peak in energy loss through the body, delivering their maximum radiation dose at or near the tumor and minimizing damage to surrounding normal tissues.

Particle therapy is also referred to more technically as hadron therapy, excluding photon and electron therapy. Neutron capture therapy, which depends on a secondary nuclear reaction, is also not considered here. Muon therapy, a rare type of particle therapy not within the categories above, has also been studied theoretically;[2] however, muons are still most commonly used for imaging, rather than therapy.[3]

Method

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Unlike electrons or X-rays, the dose from protons to tissue is maximum just over the last few millimeters of the particle's range.

Particle therapy works by aiming energetic ionizing particles at the target tumor.[4][5] These particles damage the DNA of tissue cells, ultimately causing their death. Because of their reduced ability to repair DNA, cancerous cells are particularly vulnerable to such damage.

The figure shows how beams of electrons, X-rays or protons of different energies (expressed in MeV) penetrate human tissue. Electrons have a short range and are therefore only of interest close to the skin (see electron therapy). Bremsstrahlung X-rays penetrate more deeply, but the dose absorbed by the tissue then shows the typical exponential decay with increasing thickness. For protons and heavier ions, on the other hand, the dose increases while the particle penetrates the tissue and loses energy continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions).

The advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue. This enables higher dose prescription to the tumor, theoretically leading to a higher local control rate, as well as achieving a low toxicity rate.[6]

The ions are first accelerated by means of a cyclotron or synchrotron. The final energy of the emerging particle beam defines the depth of penetration, and hence, the location of the maximum energy deposition. Since it is easy to deflect the beam by means of electro-magnets in a transverse direction, it is possible to employ a raster scan method, i.e., to scan the target area quickly, as the electron beam scans a TV tube. If, in addition, the beam energy and hence the depth of penetration is varied, an entire target volume can be covered in three dimensions, providing an irradiation exactly following the shape of the tumor. This is one of the great advantages compared to conventional X-ray therapy.

At the end of 2008, 28 treatment facilities were in operation worldwide and over 70,000 patients had been treated by means of pions,[7][8] protons and heavier ions. Most of this therapy has been conducted using protons.[9]

At the end of 2013, 105,000 patients had been treated with proton beams,[10] and approximately 13,000 patients had received carbon-ion therapy.[11]

As of April 1, 2015, for proton beam therapy, there are 49 facilities in the world, including 14 in the US with another 29 facilities under construction. For Carbon-ion therapy, there are eight centers operating and four under construction.[11] Carbon-ion therapy centers exist in Japan, Germany, Italy, and China. Two US federal agencies are hoping to stimulate the establishment of at least one US heavy-ion therapy center.[11]

Proton therapy

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Main article: Proton therapy

Proton therapy 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 (e.g., radiation therapy, or photon therapy) is that the dose of protons is deposited over a narrow range of depth, which results in minimal entry, exit, or scattered radiation dose to healthy nearby tissues. High dose rates are key in cancer treatment advancements. PSI demonstrated that for cyclotron-based proton therapy facility using momentum cooling, it is possible to achieve remarkable dose rates of 952 Gy/s and 2105 Gy/s at the Bragg peak (in water) for 70 MeV and 230 MeV beams, respectively. When combined with field-specific ridge filters, Bragg peak-based FLASH proton therapy becomes feasible.[12]

Fast-neutron therapy

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Main article: Fast neutron therapy

Fast neutron therapy utilizes high energy neutrons typically between 50 and 70 MeV to treat cancer. Most fast neutron therapy beams are produced by reactors, cyclotrons (d+Be) and linear accelerators. Neutron therapy is currently available in Germany, Russia, South Africa and the United States. In the United States, the only treatment center still operational is in Seattle, Washington. The Seattle center use a cyclotron which produces a proton beam impinging upon a beryllium target.

Carbon ion radiotherapy

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Carbon ion therapy (C-ion RT) was pioneered at the National Institute of Radiological Sciences (NIRS) in Chiba, Japan, which began treating patients with carbon ion beams in 1994. This facility was the first to utilize carbon ions clinically, marking a significant advancement in particle therapy for cancer treatment. The therapeutic advantages of carbon ions were recognized earlier, but NIRS was instrumental in establishing its clinical application.[13][14]

C-ion RT uses particles more massive than protons or neutrons.[15] Carbon ion radiotherapy has increasingly garnered scientific attention as technological delivery options have improved and clinical studies have demonstrated its treatment advantages for many cancers such as prostate, head and neck, lung, and liver cancers, bone and soft tissue sarcomas, locally recurrent rectal cancer, and pancreatic cancer, including locally advanced disease. It also has clear advantages to treat otherwise intractable hypoxic and radio-resistant cancers while opening the door for substantially hypo-fractionated treatment of normal and radio-sensitive disease.

By mid 2017, more than 15,000 patients have been treated worldwide in over 8 operational centers. Japan has been a conspicuous leader in this field. There are five heavy-ion radiotherapy facilities in operation and plans exist to construct several more facilities in the near future. In Germany this type of treatment is available at the Heidelberg Ion-Beam Therapy Center (HIT) and at the Marburg Ion-Beam Therapy Center (MIT). In Italy the National Centre of Oncological Hadrontherapy (CNAO) provides this treatment. In China, the Shanghai Proton and Heavy Ion Center (SPHIC) opened for treatments in 2015 and Austria will open a CIRT center in 2017, with centers in South Korea and Taiwan soon to open. No CIRT facility now operates in the United States but several are in various states of development. At Mayo Clinic in Jacksonville, Florida, the first carbon ion radiotherapy in North America is planned to begin in 2028.[16][17]

Biological advantages of heavy-ion radiotherapy

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From a radiation biology standpoint, there is considerable rationale to support use of heavy-ion beams in treating cancer patients. All proton and other heavy ion beam therapies exhibit a defined Bragg peak in the body so they deliver their maximum lethal dosage at or near the tumor. This minimizes harmful radiation to the surrounding normal tissues. However, carbon-ions are heavier than protons and so provide a higher relative biological effectiveness (RBE), which increases with depth to reach the maximum at the end of the beam's range. Thus the RBE of a carbon ion beam increases as the ions advance deeper into the tumor-lying region.[18] CIRT provides the highest linear energy transfer (LET) of any currently available form of clinical radiation.[19] This high energy delivery to the tumor results in many double-strand DNA breaks which are very difficult for the tumor to repair. Conventional radiation produces principally single strand DNA breaks which can allow many of the tumor cells to survive. The higher outright cell mortality produced by CIRT may also provide a clearer antigen signature to stimulate the patient's immune system.[20][21]

Particle therapy of moving targets

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The precision of particle therapy of tumors situated in thorax and abdominal region is strongly affected by the target motion. The mitigation of its negative influence requires advanced techniques of tumor position monitoring (e.g., fluoroscopic imaging of implanted radio-opaque fiducial markers or electromagnetic detection of inserted transponders) and irradiation (gating, rescanning, gated rescanning and tumor tracking).[22]

References

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Particle therapy

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Particle therapy is an advanced form of that utilizes accelerated beams of charged particles, such as protons or heavier ions like carbon, to deliver precise radiation doses to cancer tumors. Unlike conventional photon-based therapies, which deposit energy gradually along their path, particle beams exhibit a characteristic , concentrating the maximum radiation dose at a targeted depth within the tumor while minimizing exposure to surrounding healthy tissues. This physical precision, combined with the biological advantages of high (LET) and (RBE)—where protons have an RBE of approximately 1.1 and carbon ions up to 3–5—enables particle therapy to effectively treat radioresistant tumors, including those that are hypoxic, with reduced of to normal tissues. Clinically introduced in the late 20th century, with the first centers opening in 1983 in and 1990 in the United States, and carbon ion therapy beginning in 1994, particle therapy has grown substantially, with approximately 133 facilities operational worldwide as of May 2025, predominantly for protons (over 120 centers) and including carbon ion and other capabilities. By the end of 2023, over 410,000 patients had received treatment, primarily for challenging cases such as skull base chordomas (70% local control at 5 years with carbon ions), head and neck cancers (84% local control at 2 years for sinonasal malignancies with carbon ions), pediatric brain tumors, and (93% local control at 5 years with protons). Key benefits include a lower incidence of secondary cancers ( of 0.31 for protons) and reduced severe lymphopenia (from 39% to 14% with protons compared to photons), making it especially valuable for young patients and tumors near critical structures. Ongoing advancements, including active beam scanning, tumor tracking, and exploration of or oxygen ions, alongside clinical trials like the HIT-1 study, position particle therapy as a of precision , with facilities continuing to expand globally.

History

Early Developments

The discovery of the proton in 1919 by Ernest Rutherford marked a pivotal advancement in understanding subatomic particles relevant to radiation. Through experiments bombarding nitrogen atoms with alpha particles, Rutherford observed the ejection of hydrogen nuclei, which he identified as positively charged particles originating from the atomic nucleus, dubbing them protons. These findings established protons as key components of ionizing radiation, capable of interacting with matter to produce biological effects when accelerated. In 1932, James Chadwick discovered the neutron, a neutral subatomic particle, by interpreting radiation emitted from beryllium bombarded with alpha particles. Chadwick's experiments demonstrated that neutrons could penetrate matter more deeply than charged particles, offering potential for targeted radiation applications due to their uncharged nature and ability to induce nuclear reactions. This discovery complemented proton research, expanding the scope of particle-based radiation studies. The invention of the by in the early 1930s revolutionized particle acceleration for scientific and . Lawrence's device, first operational in 1931 at the , used a to spiral charged particles like protons to high energies without requiring correspondingly high voltages. By the mid-1930s, cyclotrons enabled production of accelerated particles for biological investigations, including generation through bombardment of targets, laying groundwork for exploration. Early experiments on particle biological effects began with Charles Thomson Rees Wilson's cloud chamber in 1911, which visualized ionizing particle tracks as condensation trails in supersaturated vapor, revealing interaction patterns with matter. In the 1930s and 1940s, researchers used cyclotron-produced particles, such as alpha particles and neutrons, to study tissue irradiation in plant cells and animal models, demonstrating that high (LET) particles caused denser ionization and greater cellular damage compared to low-LET X-rays. These pre-clinical studies highlighted particles' potential for precise dosing due to their distinct energy deposition profiles. A seminal contribution came in 1946 from physicist , who proposed using accelerated protons for cancer therapy in his paper "Radiological Use of Fast Protons." Wilson emphasized the —a sharp increase in energy deposition near the end of a proton's path in tissue—as a means to concentrate radiation dose within tumors while sparing surrounding healthy tissue, drawing on advancements for feasibility. This theoretical framework bridged and medicine, inspiring subsequent developments in therapeutic applications.

Clinical Milestones

The first human treatment with occurred in 1954 at the , where a patient with involving the was irradiated using protons from the 184-inch synchrocyclotron. This pioneering procedure marked the transition from preclinical experiments to clinical application, leveraging the sharp dose deposition of protons to target deep-seated tumors while sparing surrounding tissues. Dedicated proton therapy facilities emerged in the following decades, beginning with the Harvard Laboratory in 1961, which treated over 9,000 patients until its closure in 2002, primarily for ocular and intracranial conditions. Internationally, the in began clinical in 1983, marking the first dedicated facility outside research laboratories. A significant advancement came in 1990 with the opening of the Medical Center's Proton Treatment Center, the world's first hospital-based facility, which integrated into routine clinical practice and treated more than 24,000 patients over its initial decades. Key clinical trials in the 1970s demonstrated proton therapy's efficacy for ocular melanomas, with early studies at institutions like showing high local control rates exceeding 90% at five years while preserving vision in many cases. By the and , applications expanded to pediatric cancers, where trials highlighted reduced long-term toxicities compared to conventional radiotherapy, particularly for intracranial tumors like , influencing guidelines for sparing developing tissues. Regulatory milestones included U.S. (FDA) approval of systems in 1988, enabling broader commercialization and standardization of treatment protocols. Concurrently, carbon ion therapy advanced in with the 1994 launch of clinical trials at the Heavy Ion Medical Accelerator in Chiba (HIMAC) facility, which treated thousands of patients for radioresistant tumors like chordomas, establishing carbon ions as a viable option for enhanced biological effectiveness.

Physical Principles

Particle Interactions

Charged particles, such as protons and heavier ions used in particle therapy, interact with biological tissue primarily through electromagnetic forces between the incident particle and the orbital electrons of atoms. These interactions manifest as , where electrons are ejected from atoms, and excitation, where electrons are raised to higher levels without ejection. As a result, the particles lose progressively along their trajectories, creating densely ionized tracks that deposit locally in the tissue. This process dominates the energy loss mechanism for charged particles at therapeutic energies, with produced having ranges typically less than 1 mm, minimizing lateral spread. The rate of energy loss along the particle's path is quantified by the , expressed as dEdx\frac{dE}{dx}, which represents the average energy transferred per unit distance traveled. This is fundamentally described by the Bethe-Bloch formula, derived from quantum mechanical considerations of inelastic collisions. In a simplified non-relativistic form applicable to lower velocities, the formula is: dEdx=4πz2e4Nmev2\frac{dE}{dx} = \frac{4\pi z^2 e^4 N}{m_e v^2} where zz is the of the incident particle, ee is the , NN is the of electrons in the medium, mem_e is the electron rest mass, and vv is the of the particle. This expression highlights the inverse dependence on velocity squared, leading to increased energy deposition at lower speeds. The concept of (LET), often used interchangeably with dEdx\frac{dE}{dx} in this context, measures the density of energy imparted to the tissue per unit length, providing a key indicator of the spatial pattern of . Neutrons, in contrast, lack charge and thus do not experience interactions; instead, they interact with tissue via the strong nuclear force, primarily through , radiative capture, and non-elastic nuclear reactions. In , a collides with an —most efficiently with nuclei (protons) in tissue—transferring to produce protons that subsequently ionize the medium. Radiative capture occurs when a is absorbed by a nucleus, typically emitting a , as in the reaction 1H(n,γ)2H^1\text{H}(n,\gamma)^2\text{H} with a Q-value of 2.2 MeV. Nuclear reactions, such as 14N(n,p)14C^{14}\text{N}(n,p)^{14}\text{C} with a Q-value of 0.626 MeV, generate secondary charged particles like protons or alpha particles, which then deposit energy through and excitation similar to primary charged particles. These processes collectively lead to indirect energy deposition, as the neutrons themselves do not ionize directly. A notable distinction in interaction behavior arises from the nature of these mechanisms: charged particles traverse tissue along nearly straight, predictable paths with limited multiple scattering at therapeutic energies (e.g., protons above 50 MeV), enabling precise control over energy deposition depth. Neutrons, however, exhibit broader scattering due to repeated nuclear collisions, resulting in more diffuse energy transfer and requiring careful consideration of secondary particle contributions for dosimetry.

Dose Distribution Characteristics

Particle therapy exploits the unique dose deposition profile of charged particles, primarily characterized by the Bragg peak, where the majority of the energy is deposited in a sharp, localized region near the end of the particle's range in tissue. This phenomenon arises from the continuous energy loss of charged particles through interactions with matter, resulting in a relatively low and uniform dose along the initial path (the plateau region), followed by a rapid increase to a maximum at the Bragg peak and an abrupt fall-off beyond it, with virtually no dose deposited distal to the peak. Unlike conventional photon beams, which exhibit an exponential attenuation leading to significant exit doses, the Bragg peak enables precise targeting of tumors while minimizing exposure to surrounding healthy tissues. To treat tumors with finite depth and extent, the inherent narrow width of the is modulated to create a spread-out Bragg peak (SOBP), which provides a uniform dose distribution over the desired treatment volume. This is achieved by superimposing multiple beams of varying energies or using ridge filters and range modulators to shift and broaden individual Bragg peaks, effectively flattening the composite dose profile across the tumor while maintaining the sharp distal fall-off. The SOBP width and position are tailored to the target's geometry, ensuring conformal coverage without unnecessary irradiation of proximal or distal organs. The , or range RR, of charged particles in tissue is a critical for treatment planning and can be approximated using empirical power-law relations derived from models. For protons in water-equivalent tissue, a common approximation is R≈kE1.8R \approx k E^{1.8}, where EE is the initial in MeV, kk is a material-dependent constant (approximately 0.0022 cm/MeV^{1.8} for ), and the exponent 1.8 reflects the energy dependence of the in the therapeutic regime. More precise calculations integrate the Bethe-Bloch formula for −dEdx-\frac{dE}{dx}, but the power-law form provides a useful estimate for range straggling and modulation design. These dose distribution characteristics confer significant advantages in normal tissue sparing compared to photon-based radiotherapy. The absence of exit dose and the concentrated energy deposition reduce the integral dose to —the total energy absorbed by the body—by approximately 50-60% relative to intensity-modulated photon therapy for similar target coverage. For instance, in treatments for deep-seated tumors, this translates to lower doses to organs at risk, such as the heart or , potentially decreasing long-term radiation-induced toxicities.

Types of Particle Therapy

Proton Therapy

Proton therapy, the most established form of particle therapy, utilizes protons accelerated to high to deliver doses with high precision to tumors, minimizing exposure to surrounding healthy tissues. Protons are typically accelerated to ranging from 70 to 250 MeV using either cyclotrons, which provide a fixed beam that is degraded for lower energies, or synchrotrons, which allow variable extraction for direct depth control. These accelerators produce a narrow proton beam that is then transported via beamlines to treatment rooms equipped with gantries or fixed nozzles for patient positioning. Beam delivery in proton therapy involves shaping the proton beam to conform to the tumor volume, primarily through two techniques: passive scattering and . In passive scattering, upstream scatterers broaden the pristine beam into a spread-out to cover the target laterally and longitudinally, often requiring compensators and apertures for further shaping, though this method can deposit unnecessary dose in shallower tissues. In contrast, employs rapidly scanning magnets to steer narrow, energetic "" beams across the target in a layer-by-layer fashion, enabling intensity-modulated (IMPT) for highly conformal dose distributions with reduced integral dose to normal tissues. has become the dominant delivery method in modern facilities due to its versatility and efficiency for complex geometries. Proton therapy is commonly indicated for pediatric cancers, such as , where it serves as an adjuvant treatment following surgical resection to target residual disease while sparing developing organs. It is also frequently used for localized and head and neck tumors, particularly those adjacent to critical structures like the or salivary glands. Evidence from comparative modeling and cohort studies indicates a reduction in secondary cancer risk with compared to conventional photon-based radiotherapy in pediatric patients, attributed to lower out-of-field dose. Treatment courses typically involve daily fractions of 1.8-2.2 Gy (, RBE), delivered over 20-40 sessions to achieve total doses of 50-70 Gy (RBE), depending on the tumor site and . For instance, protocols often use 23.4 Gy (RBE) craniospinal followed by a boost to the tumor bed, while treatments may total 76-80 Gy (RBE) in 38-40 fractions. These regimens leverage the sharp distal fall-off of the to escalate tumor dose without proportionally increasing normal tissue exposure. Clinical outcomes from meta-analyses demonstrate that achieves local control rates equivalent to intensity-modulated (IMRT) across indications, with 5-year rates exceeding 80-90% for favorable-risk and pediatric tumors. It is associated with significantly lower acute and late toxicities, including reduced rates of grade 2+ ( 0.44) and in head and neck cancers, and decreased genitourinary toxicity in cases. Prospective data from facilities like the proton therapy complex further support these findings, showing promising disease control with acceptable toxicity profiles in challenging sites such as skull-base tumors.

Neutron Therapy

Fast neutron therapy involves the use of high-energy neutrons, typically in the range of 40-70 MeV, produced by bombarding targets with protons accelerated in cyclotrons via the reaction p + Be → n + X. This method generates a mixed neutron-photon beam suitable for , with neutrons offering deeper penetration than lower-energy alternatives due to reduced in tissue. Historically, has been indicated for radioresistant tumors such as malignant tumors (e.g., of the ) and sarcomas that show poor response to conventional radiotherapy. In the , Radiation Therapy Oncology Group (RTOG) trials, including a randomized RTOG-MRC study, demonstrated improved local control rates for inoperable or recurrent tumors compared to photons, with neutron therapy achieving up to 56% local-regional control in unresectable cases. Similarly, for inoperable sarcomas, neutron therapy provided better outcomes in local control for advanced disease, though overall survival benefits were marginal. Delivery of fast neutron therapy presents challenges due to the beam's physical properties, including increased that results in a broader penumbra and less sharp dose fall-off compared to beams, necessitating the use of compensators to shape the dose distribution and improve conformity. Typical fractionation involves 1.5-2.0 Gy (physical dose) per fraction, often delivered in 3-5 sessions weekly to account for the higher (RBE) of neutrons, with total doses adjusted based on institutional RBE values around 3 for tumor effects. The adoption of fast neutron therapy has declined significantly since the , primarily due to elevated toxicity profiles, including 10-15% rates of severe late effects such as radiation-induced , , and secondary malignancies in normal tissues like brain , where RBE can reach 5. These complications, observed in RTOG and other trials, outweighed the benefits for most indications, leading to the closure of many facilities; by the , only a few centers remain operational globally, including the in the , following closures like the Tomsk facility in .

Heavy Ion Therapy

Heavy ion therapy utilizes accelerated ions heavier than protons, such as , , and oxygen, to treat cancer with enhanced precision and biological effectiveness due to their higher (LET). ions are the most commonly used, providing a balance of and density suitable for deep-seated tumors. Facilities like the Ion-Beam Therapy Center (HIT) in and the National Institutes for Quantum Science and Technology (QST) in employ synchrotrons to accelerate these ions to energies typically ranging from 100 to 400 MeV/u, enabling beam ranges of up to 30 cm in tissue. This modality is particularly indicated for radioresistant cancers, including chordomas and adenoid cystic carcinomas, where conventional radiotherapy often yields suboptimal outcomes. Japanese clinical trials at QST have demonstrated promising results for skull base tumors, with 5-year overall survival rates of 76-88% for chordomas and adenoid cystic carcinomas treated with carbon ions. These enhanced biological effects stem from the ions' ability to produce densely ionizing tracks that cause complex DNA damage less amenable to cellular repair, making heavy ion therapy effective against tumors historically resistant to X-ray or proton beams. Beam delivery in heavy ion therapy relies on raster scanning, an active technique that superimposes numerous narrow beams to achieve precise three-dimensional dose to the tumor . This method allows for intensity-modulated , minimizing exposure to surrounding healthy tissues. The spread-out (SOBP) is tailored to the tumor's depth profile using energy degraders and compensators, ensuring uniform dosing across irregular shapes while leveraging the sharp distal fall-off similar to . As of 2025, over 50,000 patients have been treated with heavy ion therapy worldwide, predominantly in (e.g., ) and (e.g., ), reflecting the concentration of operational facilities in these regions. Indications are expanding beyond traditional sites like the skull base to include and liver cancers, supported by ongoing clinical trials that explore carbon ion efficacy in non-small cell and , where motion management and hypofractionation enhance applicability.

Biological Effects

Relative Biological Effectiveness

The relative biological effectiveness (RBE) is defined as the ratio of the absorbed dose of a reference radiation, typically 250 kV X-rays or high-energy photons, to the absorbed dose of the test radiation (such as protons, neutrons, or heavy ions) required to produce the same level of biological effect, often quantified by metrics like cell survival or tumor control. In particle therapy, RBE quantifies the enhanced biological impact of charged particles compared to conventional photon radiotherapy, where the reference RBE is set to 1.0. Typical RBE values are approximately 1.1 for protons, 3–5 for neutrons, and 2–5 for carbon ions, reflecting their varying abilities to induce DNA damage and cell death. RBE is influenced by several factors, primarily the , which measures the energy deposited per unit length of particle track and increases toward the end of the particle's range. Higher LET leads to denser ionization and more complex DNA lesions, elevating RBE in a non-linear fashion that depends on particle type, energy, , and biological endpoint (e.g., early vs. late tissue effects). More sophisticated models account for additional variables like track structure. Other influences include oxygen levels (hypoxic cells show higher RBE) and tissue sensitivity, but LET remains the dominant predictor in treatment planning. RBE is measured using in vitro assays, such as clonogenic survival curves that assess cell reproductive capacity after irradiation, and in vivo models evaluating tissue responses like skin reactions or tumor growth delay. These experimental data inform clinical applications, where proton RBE is conventionally fixed at 1.1 for simplicity across the beam path, despite variations. Recent advancements as of 2024 include the exploration and partial clinical implementation of variable RBE models for protons to better account for LET dependence. For heavy ions like carbon, RBE is variable and position-dependent, often calculated using the Local Effect Model (LEM), which predicts biological effects based on local energy deposition and nanoscale damage patterns without relying on target fragmentation. Uncertainties in RBE arise from its dependence on depth within the spread-out (SOBP), where LET—and thus RBE—increases distally, potentially leading to over- or under-dosing if not modeled accurately. This position-dependent variation, combined with inter-patient biological differences, contributes to a 10–30% in proton RBE-weighted dose calculations, prompting ongoing refinements in treatment planning systems through advanced models and simulations.

Advantages Over Conventional Radiotherapy

Particle therapy offers distinct advantages over conventional -based radiotherapy, such as intensity-modulated (IMRT) or stereotactic body (SBRT), primarily through superior dose conformity and reduced exposure to surrounding healthy tissues, leading to lower rates of treatment-related complications while maintaining or improving tumor control. These benefits stem from the sharp dose fall-off at the in particle beams, which minimizes the integral dose to normal tissues compared to the broader penumbra and exit dose in beams. Additionally, the higher (RBE) of particles, particularly heavier ions, enhances cell killing efficiency in certain tumor environments. One key advantage is the reduced normal tissue complication probability (NTCP) associated with particle therapy, particularly for tumors near critical structures. For instance, in the treatment of skull base chordomas, has been shown to lower the NTCP for brainstem necrosis by approximately 47% relative to approaches through optimized planning that spares the more effectively. This dosimetric superiority translates to a 1.5- to 4-fold reduction in the volume of normal tissue receiving low-to-intermediate doses, thereby decreasing the risk of late toxicities such as cranial neuropathy or optic damage. Particle therapy also demonstrates improved tumor control for challenging sites like base-of-skull tumors, where precise targeting is essential. Meta-analyses of comparative studies indicate that achieves equivalent or superior efficacy to IMRT, with higher 5-year overall survival (P=0.038) and rates, alongside significantly reduced toxicity profiles. For skull base chondrosarcomas, particle beam therapy yields better compared to photon radiotherapy, highlighting its role in enhancing locoregional control without escalating adverse events. In pediatric , particle provides substantial long-term benefits by decreasing the integral dose to developing organs, which lowers the risk of secondary malignancies—a critical concern given the heightened of children. Modeling studies estimate that can reduce this risk by a factor of 2 to 10 relative to photon , potentially translating to an absolute risk reduction of 5-10% over decades of follow-up, depending on tumor site and age at treatment. This preservation of healthy tissue supports improved and survivorship outcomes in young patients. For heavy ion therapy, such as carbon ion radiotherapy, the advantages extend to biologically resistant tumors, including those with hypoxic or slow-growing regions, due to the high that induces clustered DNA damage less dependent on oxygenation. Unlike photons, which rely on an oxygen enhancement ratio (OER) of 2.5-3.5—making hypoxic cells up to three times more radioresistant—heavy ions exhibit an OER of approximately 1-1.5, enabling more effective killing of oxygen-poor tumor cells without the need for radiosensitizers. This property is particularly beneficial for radioresistant malignancies like sarcomas or glioblastomas, where conventional radiotherapy often falls short.

Clinical Challenges

Targeting Moving Tumors

Organ motion, primarily driven by respiration and cardiac activity, poses significant challenges in particle for thoracic and abdominal tumors. Respiratory motion can exhibit amplitudes of up to 2-3 cm in the superior-inferior direction for tumors, while cardiac motion contributes additional displacements on the order of 2 mm. These dynamics lead to range uncertainties of several millimeters in , arising from variations in tissue and path length that alter the position—for instance, up to 5-10 mm without mitigation in cases due to changes. In heavy , similar effects are amplified due to the steeper dose fall-off, exacerbating potential underdosage of the target or overdosing of healthy tissues. To model and mitigate this motion, four-dimensional computed tomography (4D-CT) is widely employed to capture the full extent of tumor displacement across respiratory phases, enabling the creation of motion-inclusive treatment plans. Common mitigation techniques include respiratory gating, where the beam is delivered only during a specific phase such as end-exhale to minimize residual motion, and repainting (or rescanning), which involves multiple deliveries of the same beam energy layers per fraction to statistically average out interplay effects between beam scanning and tumor movement. These approaches reduce dosimetric errors, with gating shown to improve target coverage and decrease uncertainties in simulated scenarios. Advanced real-time tracking methods further enhance precision, particularly for scanned beams. Ionization chamber arrays, such as the MatriXX PT/ONE, facilitate intrafractional monitoring and adaptive adjustments during delivery. For heavy ion therapy, prompt gamma provides non-invasive, real-time verification of the range by detecting secondary radiation emitted during interactions, allowing for immediate corrections to motion-induced shifts. Experimental studies have validated these techniques, showing improved target coverage in dynamic phantoms mimicking respiratory patterns. Despite these advancements, residual uncertainties persist in the spread-out (SOBP), where motion can distort the uniform dose plateau by several millimeters even after mitigation. Ongoing clinical trials for liver and cancers, including those evaluating 4D-optimized proton plans with gating, confirm the feasibility of these strategies but highlight drawbacks such as prolonged treatment times—often doubled due to duty cycles of 30-50% in gating. Recent advancements as of 2025 include AI-based motion tracking and algorithms for real-time intrafractional , improving accuracy in adaptive delivery for moving tumors. These efforts underscore the need for integrated motion to fully realize the precision advantages of particle in mobile targets.

Treatment Planning and Delivery

Treatment planning in particle therapy begins with advanced imaging integration to accurately delineate the tumor and surrounding organs at risk (OARs). Computed tomography (CT) scans are the cornerstone for anatomical mapping, providing electron density information essential for dose calculations, while magnetic resonance imaging (MRI) enhances soft-tissue contrast for precise tumor boundary definition, and positron emission tomography (PET) aids in identifying metabolically active regions to guide target volumes. These modalities are fused into a single planning dataset to create a three-dimensional model of the patient's anatomy. Monte Carlo simulations are employed for dose calculations, simulating particle interactions at a probabilistic level to account for tissue heterogeneities such as bone, air cavities, and varying densities, which can significantly affect beam range and lateral penumbra in proton and heavy ion therapies. This method outperforms analytical pencil beam algorithms by providing higher accuracy in heterogeneous media, with studies showing agreement within 2% compared to measurements in phantoms. Optimization of the treatment plan follows imaging, utilizing inverse planning techniques tailored to delivery modalities like pencil beam scanning (), where numerous narrow beams are modulated in intensity and energy to sculpt the dose distribution. The goal is to achieve robust coverage of the planning target volume (PTV), typically ensuring that at least 95% of the prescribed dose reaches 95% of the PTV (D95 > 95%), while minimizing doses to OARs through constraints such as maximum dose limits or mean dose reductions. Intensity-modulated particle therapy (IMPT) extends this by optimizing spot weights via gradient-based algorithms, enabling conformal dose delivery that spares healthy tissues more effectively than passive scattering methods, as demonstrated in clinical trials where OAR doses were reduced by 20-30% without compromising tumor control. Delivery systems in particle therapy vary by facility design, with gantries providing 360-degree rotation for multi-angle beam incidence to optimize dose conformity, particularly advantageous for deep-seated tumors requiring non-coplanar geometries, whereas fixed-beam nozzles limit flexibility but reduce costs and complexity for standard setups. Robotic positioning systems, such as six-degree-of-freedom couches, ensure sub-millimeter patient alignment by integrating with , allowing for precise setup verification. Quality assurance is integral, incorporating daily image-guided radiotherapy (IGRT) using orthogonal X-rays or cone-beam CT to correct positional deviations, and in-vivo via prompt gamma or PET to monitor real-time dose deposition and detect range shifts during treatment. To address uncertainties inherent in particle therapy, robustness planning is incorporated into the optimization process, explicitly accounting for setup errors of 2-3 mm and range uncertainties of 3-5% arising from inaccuracies, anatomical changes, or beam calibration variations. Worst-case scenario optimization evaluates multiple perturbed scenarios—such as shifts in position or proton ratios—and adjusts the plan to maintain PTV coverage across them, often using frameworks that minimize the maximum deviation in dose metrics. This approach has been shown to improve plan robustness, with DVH band widths reduced by up to 50% in proton plans compared to conventional methods, enhancing clinical reliability. For cases involving motion-specific adaptations, such as respiratory gating, these are briefly integrated into the delivery workflow to further refine robustness.

Global Implementation

Major Facilities

As of October 2025, 92 proton therapy facilities operate worldwide, equipped with 223 treatment rooms, providing advanced radiation options for various cancers. These centers primarily use or accelerators to deliver proton beams, with many focusing on pediatric cases, tumors, and due to the therapy's precision in sparing healthy tissue. A prominent example is the in , USA, which features four gantries and treats approximately 2,200 patients annually following recent expansions, representing 30-40% more than comparable U.S. centers. Another key facility is the (PSI) in Villigen, , renowned for its specialization in ocular tumor treatment using a dedicated OPTIS2 unit; since 1984, PSI has treated over 8,200 eye cancer patients with protons, preserving vision in many cases. Heavy ion therapy facilities remain fewer, with 14 operational centers globally, mostly utilizing carbon ions for radioresistant tumors such as sarcomas and head-and-neck cancers. The National Institutes for Quantum Science and Technology (QST) Hospital, formerly the National Ion Beam Cancer Therapy Center in Chiba, Japan, stands out as a pioneer, having treated over 15,000 patients with carbon ions since 1994 and handling more than 800 cases annually. In Europe, the Heidelberg Ion-Beam Therapy Center (HIT) in Germany offers mixed-ion capabilities, including protons, carbon, and helium ions via synchrotron delivery; operational since 2009, it provides two fixed-beam rooms and one gantry, treating complex cases like chordomas with high precision. Neutron therapy is no longer active for routine clinical use worldwide, with capabilities limited to historical programs or research trials targeting tumors and soft-tissue sarcomas where conventional radiotherapy falls short. In the United States, the , affiliated with , maintains historical neutron capabilities from earlier programs but supports primarily ongoing trials with low patient volume compared to proton or facilities. Global capacity for particle therapy has expanded significantly, with cumulative treatments exceeding 450,000 patients by 2025, up from earlier estimates around 2020, and projections indicating over 500,000 by 2030 driven by new constructions. Notable recent developments include the Shanghai Proton and Heavy Ion Center (SPHIC) in China, which combines proton and carbon ion beams across three fixed rooms and one gantry; operational since 2015, it has treated nearly 8,000 patients as of May 2025 and is set to become one of the world's largest facilities upon full expansion. In South Korea, a new proton center is under development, with installations beginning in 2028 to enhance regional access.

Access and Economic Factors

Particle therapy faces significant barriers to widespread adoption due to its high costs and uneven global distribution. The construction of a particle facility typically requires an investment of $100 million to $300 million, depending on whether it supports protons, carbon ions, or both, with annual maintenance costs driven by the complex accelerator systems often exceeding $20 million. Per-patient treatment costs for particle therapy range from $30,000 to $50,000, substantially higher than the $10,000 to $20,000 for intensity-modulated radiation therapy (IMRT), primarily owing to the specialized equipment and operational demands of particle accelerators. Insurance coverage for particle therapy varies by region and indication. In and many European countries, systems provide full reimbursement for approved indications, such as certain pediatric cancers and skull base tumors, facilitating broader access. In the United States, coverage is more limited; Medicare has covered since 2015 for specific conditions like and pediatric tumors, but carbon ion therapy remains largely uncovered, leaving many patients reliant on private with variable policies. Geographic disparities exacerbate access issues, with approximately 80% of the world's approximately 106 particle therapy centers located in high-income countries, primarily in the United States, , and . This concentration means fewer than 1% of global cancer patients receive particle therapy annually, despite an estimated 20 million new cases worldwide each year, imposing significant travel burdens on rural or low-income populations who must often relocate for weeks-long treatments. Efforts to improve equity include international collaborations such as the European Union's PARTNER project, which focuses on training personnel and fostering knowledge exchange to expand capabilities in underserved regions. Additionally, into compact accelerators aims to reduce facility costs by minimizing needs, potentially enabling more centers in middle-income countries through smaller, more affordable designs. Recent expansions include new facilities in and becoming operational in 2025.

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