Fast neutron therapy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/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, three treatment centers are operational in Seattle, Washington, Detroit, Michigan and Batavia, Illinois. The Detroit and Seattle centers use a cyclotron which produces a proton beam impinging upon a beryllium target; the Batavia center at Fermilab uses a proton linear accelerator.

Advantages

Radiation therapy kills cancer cells in two ways depending on the effective energy of the radiative source. The amount of energy deposited as the particles traverse a section of tissue is referred to as the linear energy transfer (LET). X-rays produce low LET radiation, and protons and neutrons produce high LET radiation. Low LET radiation damages cells predominantly through the generation of reactive oxygen species, see free radicals. The neutron is uncharged and damages cells by direct effect on nuclear structures. Malignant tumors tend to have low oxygen levels and thus can be resistant to low LET radiation. This gives an advantage to neutrons in certain situations. One advantage is a generally shorter treatment cycle. To kill the same number of cancerous cells, neutrons require one third the effective dose as protons. Another advantage is the established ability of neutrons to better treat some cancers, such as salivary gland, adenoid cystic carcinomas and certain types of brain tumors, especially high-grade gliomas. 

LET

Comparison of Low LET electrons and High LET electrons

When therapeutic energy X-rays (1 to 25 MeV) interact with cells in human tissue, they do so mainly by Compton interactions, and produce relatively high energy secondary electrons. These high energy electrons deposit their energy at about 1 keV/µm. By comparison, the charged particles produced at a site of a neutron interaction may deliver their energy at a rate of 30–80 keV/µm. The amount of energy deposited as the particles traverse a section of tissue is referred to as the linear energy transfer (LET). X-rays produce low LET radiation, and neutrons produce high LET radiation.

Because the electrons produced from X-rays have high energy and low LET, when they interact with a cell typically only a few ionizations will occur. It is likely then that the low LET radiation will cause only single strand breaks of the DNA helix. Single strand breaks of DNA molecules can be readily repaired, and so the effect on the target cell is not necessarily lethal. By contrast, the high LET charged particles produced from neutron irradiation cause many ionizations as they traverse a cell, and so double-strand breaks of the DNA molecule are possible. DNA repair of double-strand breaks are much more difficult for a cell to repair, and more likely to lead to cell death.

DNA repair mechanisms are quite efficient, and during a cell's lifetime many thousands of single strand DNA breaks will be repaired. A sufficient dose of ionizing radiation, however, delivers so many DNA breaks that it overwhelms the capability of the cellular mechanisms to cope. 

Heavy ion therapy (e.g. carbon ions) makes use of the similarly high LET of ¹²C⁶⁺ ions.

Because of the high LET, the relative radiation damage (relative biological effect or RBE) of fast neutrons is 4 times that of X-rays, meaning 1 rad of fast neutrons is equal to 4 rads of X-rays. The RBE of neutrons is also energy dependent, so neutron beams produced with different energy spectra at different facilities will have different RBE values.

Oxygen effect

The presence of oxygen in a cell acts as a radiosensitizer, making the effects of the radiation more damaging. Tumor cells typically have a lower oxygen content than normal tissue. This medical condition is known as tumor hypoxia and therefore the oxygen effect acts to decrease the sensitivity of tumor tissue. The oxygen effect may be quantitatively described by the Oxygen Enhancement Ratio (OER). Generally it is believed that neutron irradiation overcomes the effect of tumor hypoxia, although there are counterarguments. 

Clinical uses

The efficacy of neutron beams for use on prostate cancer has been shown through randomized trials. Fast neutron therapy has been applied successfully against salivary gland tumors. Adenoid cystic carcinomas have also been treated. Various other head and neck tumors have been examined.

Side effects

No cancer therapy is without the risk of side effects. Neutron therapy is a very powerful nuclear scalpel that has to be utilized with exquisite care. For instance, some of the most remarkable cures it has been able to achieve are with cancers of the head and neck. Many of these cancers cannot effectively be treated with other therapies. However, neutron damage to nearby vulnerable areas such as the brain and sensory neurons can produce irreversible brain atrophy, blindness, etc. The risk of these side effects can be greatly mitigated by several techniques, but they cannot be totally eliminated. Moreover, some patients are more susceptible to such side effects than others and this cannot be predicted in advance. The patient ultimately must decide whether the advantages of a possibly lasting cure outweigh the risks of this treatment when faced with an otherwise incurable cancer.

Fast neutron centers

Several centers around the world have used fast neutrons for treating cancer. Due to lack of funding and support, at present only three are active in the USA. The University of Washington and the Gershenson Radiation Oncology Center operate fast neutron therapy beams and both are equipped with a Multi-Leaf Collimator (MLC) to shape the neutron beam.

University of Washington

The Radiation Oncology Department operates a proton cyclotron that produces fast neutrons from directing 50.5MeV protons onto a beryllium target. The UW Cyclotron is equipped with a gantry mounted delivery system an MLC to produce shaped fields. The UW Neutron system is referred to as the Clinical Neutron Therapy System (CNTS). The CNTS is typical of most neutron therapy systems. A large, well shielded building is required to cut down on radiation exposure to the general public and to house the necessary equipment.

Univ. of Washington CNTS

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  UW Cyclotron
  
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  Multi-Leaf Collimator (MLC) used to shape the neutron beam
  
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  Schematic of a treatment field delivery. The patient couch has been rotated, along with the gantry so the neutron beam will enter obliquely, to give maximum sparing of normal tissue.
  
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  Example of a treatment neutron field collimated using a neutron MLC
  

A beamline transports the proton beam from the cyclotron to a gantry system. The gantry system contains magnets for deflecting and focusing the proton beam onto the beryllium target. The end of the gantry system is referred to as the head, and contains dosimetry systems to measure the dose, along with the MLC and other beam shaping devices. The advantage of having a beam transport and gantry are that the cyclotron can remain stationary, and the radiation source can be rotated around the patient. Along with varying the orientation of the treatment couch which the patient is positioned on, variation of the gantry position allows radiation to be directed from virtually any angle, allowing sparing of normal tissue and maximum radiation dose to the tumor.

During treatment, only the patient remains inside the treatment room (called a vault) and the therapists will remotely control the treatment, viewing the patient via video cameras. Each delivery of a set neutron beam geometry is referred to as a treatment field or beam. The treatment delivery is planned to deliver the radiation as effectively as possible, and usually results in fields that conform to the shape of the gross target, with any extension to cover microscopic disease. 

Karmanos Cancer Center / Wayne State University

The neutron therapy facility at the Gershenson Radiation Oncology Center at Karmanos Cancer Center/Wayne State University (KCC/WSU) in Detroit bears some similarities to the CNTS at the University of Washington, but also has many unique characteristics. This unit was decommissioned in 2011. 

MLC on KCC/WSU cyclotron

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  Schematic of MLC
  
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  Photo of the MLC
  
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  Schematic of the KCC/WSU gantry mounted superconducting cyclotron
  

While the CNTS accelerates protons, the KCC facility produces its neutron beam by accelerating 48.5 MeV deuterons onto a beryllium target. This method produces a neutron beam with depth dose characteristics roughly similar to those of a 4 MV photon beam. The deuterons are accelerated using a gantry mounted superconducting cyclotron (GMSCC), eliminating the need for extra beam steering magnets and allowing the neutron source to rotate a full 360° around the patient couch.

The KCC facility is also equipped with an MLC beam shaping device, the only other neutron therapy center in the USA besides the CNTS. The MLC at the KCC facility has been supplemented with treatment planning software that allows for the implementation of Intensity Modulated Neutron Radiotherapy (IMNRT), a recent advance in neutron beam therapy which allows for more radiation dose to the targeted tumor site than 3-D neutron therapy.

KCC/WSU has more experience than anyone in the world using neutron therapy for prostate cancer, having treated nearly 1,000 patients during the past 10 years. 

Fermilab / Northern Illinois University

The Fermilab neutron therapy center first treated patients in 1976, and since that time has treated over 3,000 patients. In 2004, the Northern Illinois University began managing the center. The neutrons produced by the linear accelerator at Fermilab have the highest energies available in the US and among the highest in the world

Particle therapy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Particle_therapy

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 2012 is proton therapy.

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 attempted.

Method

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. 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. 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.

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 like 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, protons and heavier ions. Most of this therapy has been conducted using protons.

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

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

Proton therapy

Main article: Proton therapy

Fast-neutron therapy

Main article: Fast neutron therapy

Carbon-ion radiotherapy

Carbon ion therapy (CIRT) uses particles more massive than protons or neutrons. 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. Austria will open a CIRT center in 2017, with centers in South Korea, Taiwan, and China soon to open. No CIRT facility now operates in the United States but several are in various states of development.

Biological advantages of heavy-ion radiotherapy

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. CIRT provides the highest linear energy transfer (LET) of any currently available form of clinical radiation. 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.

Particle therapy of moving targets

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).

Radiation therapy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Radiation_therapy

 

Radiation therapy
Radiation therapy of the pelvis, using a Varian Clinac iX linear accelerator. Lasers and a mould under the legs are used to determine exact position.
ICD-10-PCS	D
ICD-9-CM	92.2-92.3
MeSH	D011878
OPS-301 code	8–52
MedlinePlus	001918

Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor (for example, early stages of breast cancer). Radiation therapy is synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers. The subspecialty of oncology concerned with radiotherapy is called radiation oncology.

Radiation therapy is commonly applied to the cancerous tumor because of its ability to control cell growth. Ionizing radiation works by damaging the DNA of cancerous tissue leading to cellular death. To spare normal tissues (such as skin or organs which radiation must pass through to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose there than in the surrounding, healthy tissue. Besides the tumour itself, the radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumor, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumor to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumor position.

Radiation oncology is the medical specialty concerned with prescribing radiation, and is distinct from radiology, the use of radiation in medical imaging and diagnosis. Radiation may be prescribed by a radiation oncologist with intent to cure ("curative") or for adjuvant therapy. It may also be used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). It is also common to combine radiation therapy with surgery, chemotherapy, hormone therapy, immunotherapy or some mixture of the four. Most common cancer types can be treated with radiation therapy in some way.

The precise treatment intent (curative, adjuvant, neoadjuvant therapeutic, or palliative) will depend on the tumor type, location, and stage, as well as the general health of the patient. Total body irradiation (TBI) is a radiation therapy technique used to prepare the body to receive a bone marrow transplant. Brachytherapy, in which a radioactive source is placed inside or next to the area requiring treatment, is another form of radiation therapy that minimizes exposure to healthy tissue during procedures to treat cancers of the breast, prostate and other organs. Radiation therapy has several applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, acoustic neuromas, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, and prevention of keloid scar growth, vascular restenosis, and heterotopic ossification. The use of radiation therapy in non-malignant conditions is limited partly by worries about the risk of radiation-induced cancers.

Medical uses

Radiation therapy for a patient with a diffuse intrinsic pontine glioma, with radiation dose color-coded.

Different cancers respond to radiation therapy in different ways.

The response of a cancer to radiation is described by its radiosensitivity. Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation. These include leukemias, most lymphomas and germ cell tumors. The majority of epithelial cancers are only moderately radiosensitive, and require a significantly higher dose of radiation (60-70 Gy) to achieve a radical cure. Some types of cancer are notably radioresistant, that is, much higher doses are required to produce a radical cure than may be safe in clinical practice. Renal cell cancer and melanoma are generally considered to be radioresistant but radiation therapy is still a palliative option for many patients with metastatic melanoma. Combining radiation therapy with immunotherapy is an active area of investigation and has shown some promise for melanoma and other cancers.

It is important to distinguish the radiosensitivity of a particular tumor, which to some extent is a laboratory measure, from the radiation "curability" of a cancer in actual clinical practice. For example, leukemias are not generally curable with radiation therapy, because they are disseminated through the body. Lymphoma may be radically curable if it is localised to one area of the body. Similarly, many of the common, moderately radioresponsive tumors are routinely treated with curative doses of radiation therapy if they are at an early stage. For example: non-melanoma skin cancer, head and neck cancer, breast cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer. Metastatic cancers are generally incurable with radiation therapy because it is not possible to treat the whole body.

Before treatment, a CT scan is often performed to identify the tumor and surrounding normal structures. The patient receives small skin marks to guide the placement of treatment fields. Patient positioning is crucial at this stage as the patient will have to be set-up in the identical position during treatment. Many patient positioning devices have been developed for this purpose, including masks and cushions which can be molded to the patient.

The response of a tumor to radiation therapy is also related to its size. Due to complex radiobiology, very large tumors respond less well to radiation than smaller tumors or microscopic disease. Various strategies are used to overcome this effect. The most common technique is surgical resection prior to radiation therapy. This is most commonly seen in the treatment of breast cancer with wide local excision or mastectomy followed by adjuvant radiation therapy. Another method is to shrink the tumor with neoadjuvant chemotherapy prior to radical radiation therapy. A third technique is to enhance the radiosensitivity of the cancer by giving certain drugs during a course of radiation therapy. Examples of radiosensitizing drugs include: Cisplatin, Nimorazole, and Cetuximab.

The impact of radiotherapy varies between different types of cancer and different groups. For example, for breast cancer after breast-conserving surgery, radiotherapy has been found to halve the rate at which the disease recurs.

Side effects

Radiation therapy is in itself painless. Many low-dose palliative treatments (for example, radiation therapy to bony metastases) cause minimal or no side effects, although short-term pain flare-up can be experienced in the days following treatment due to oedema compressing nerves in the treated area. Higher doses can cause varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after re-treatment (cumulative side effects). The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose, fractionation, concurrent chemotherapy), and the patient.

Most side effects are predictable and expected. Side effects from radiation are usually limited to the area of the patient's body that is under treatment. Side effects are dose- dependent; for example higher doses of head and neck radiation can be associated with cardiovascular complications, thyroid dysfunction, and pituitary axis dysfunction. Modern radiation therapy aims to reduce side effects to a minimum and to help the patient understand and deal with side effects that are unavoidable.

The main side effects reported are fatigue and skin irritation, like a mild to moderate sun burn. The fatigue often sets in during the middle of a course of treatment and can last for weeks after treatment ends. The irritated skin will heal, but may not be as elastic as it was before.

Acute side effects

Nausea and vomiting

This is not a general side effect of radiation therapy, and mechanistically is associated only with treatment of the stomach or abdomen (which commonly react a few hours after treatment), or with radiation therapy to certain nausea-producing structures in the head during treatment of certain head and neck tumors, most commonly the vestibules of the inner ears. As with any distressing treatment, some patients vomit immediately during radiotherapy, or even in anticipation of it, but this is considered a psychological response. Nausea for any reason can be treated with antiemetics.

 

Damage to the epithelial surfaces

Epithelial surfaces may sustain damage from radiation therapy. Depending on the area being treated, this may include the skin, oral mucosa, pharyngeal, bowel mucosa and ureter. The rates of onset of damage and recovery from it depend upon the turnover rate of epithelial cells. Typically the skin starts to become pink and sore several weeks into treatment. The reaction may become more severe during the treatment and for up to about one week following the end of radiation therapy, and the skin may break down. Although this moist desquamation is uncomfortable, recovery is usually quick. Skin reactions tend to be worse in areas where there are natural folds in the skin, such as underneath the female breast, behind the ear, and in the groin.

 

Mouth, throat and stomach sores

If the head and neck area is treated, temporary soreness and ulceration commonly occur in the mouth and throat. If severe, this can affect swallowing, and the patient may need painkillers and nutritional support/food supplements. The esophagus can also become sore if it is treated directly, or if, as commonly occurs, it receives a dose of collateral radiation during treatment of lung cancer. When treating liver malignancies and metastases, it is possible for collateral radiation to cause gastric, stomach or duodenal ulcers This collateral radiation is commonly caused by non-targeted delivery (reflux) of the radioactive agents being infused.^[16] Methods, techniques and devices are available to lower the occurrence of this type of adverse side effect.

 

Intestinal discomfort

The lower bowel may be treated directly with radiation (treatment of rectal or anal cancer) or be exposed by radiation therapy to other pelvic structures (prostate, bladder, female genital tract). Typical symptoms are soreness, diarrhoea, and nausea.

 

Swelling

As part of the general inflammation that occurs, swelling of soft tissues may cause problems during radiation therapy. This is a concern during treatment of brain tumors and brain metastases, especially where there is pre-existing raised intracranial pressure or where the tumor is causing near-total obstruction of a lumen (e.g., trachea or main bronchus). Surgical intervention may be considered prior to treatment with radiation. If surgery is deemed unnecessary or inappropriate, the patient may receive steroids during radiation therapy to reduce swelling.

 

Infertility

The gonads (ovaries and testicles) are very sensitive to radiation. They may be unable to produce gametes following direct exposure to most normal treatment doses of radiation. Treatment planning for all body sites is designed to minimize, if not completely exclude dose to the gonads if they are not the primary area of treatment.

Late side effects

Late side effects occur months to years after treatment and are generally limited to the area that has been treated. They are often due to damage of blood vessels and connective tissue cells. Many late effects are reduced by fractionating treatment into smaller parts.

Fibrosis

Tissues which have been irradiated tend to become less elastic over time due to a diffuse scarring process.

 

Epilation

Epilation (hair loss) may occur on any hair bearing skin with doses above 1 Gy. It only occurs within the radiation field/s. Hair loss may be permanent with a single dose of 10 Gy, but if the dose is fractionated permanent hair loss may not occur until dose exceeds 45 Gy.

 

Dryness

The salivary glands and tear glands have a radiation tolerance of about 30 Gy in 2 Gy fractions, a dose which is exceeded by most radical head and neck cancer treatments. Dry mouth (xerostomia) and dry eyes (xerophthalmia) can become irritating long-term problems and severely reduce the patient's quality of life. Similarly, sweat glands in treated skin (such as the armpit) tend to stop working, and the naturally moist vaginal mucosa is often dry following pelvic irradiation.

 

Lymphedema

Lymphedema, a condition of localized fluid retention and tissue swelling, can result from damage to the lymphatic system sustained during radiation therapy. It is the most commonly reported complication in breast radiation therapy patients who receive adjuvant axillary radiotherapy following surgery to clear the axillary lymph nodes.

 

Cancer

Radiation is a potential cause of cancer, and secondary malignancies are seen in some patients. Cancer survivors are already more likely than the general population to develop malignancies due to a number of factors including lifestyle choices, genetics, and previous radiation treatment. It is difficult to directly quantify the rates of these secondary cancers from any single cause. Studies have found radiation therapy as the cause of secondary malignancies for only a small minority of patients. New techniques such as proton beam therapy and carbon ion radiotherapy which aim to reduce dose to healthy tissues will lower these risks. It starts to occur 4 - 6 years following treatment, although some haematological malignancies may develop within 3 years. In the vast majority of cases, this risk is greatly outweighed by the reduction in risk conferred by treating the primary cancer even in pediatric malignancies which carry a higher burden of secondary malignancies.

 

Cardiovascular disease

Radiation can increase the risk of heart disease and death as observed in previous breast cancer RT regimens. Therapeutic radiation increases the risk of a subsequent cardiovascular event (i.e., heart attack or stroke) by 1.5 to 4 times a person's normal rate, aggravating factors included. The increase is dose dependent, related to the RT's dose strength, volume and location.

Cardiovascular late side effects have been termed radiation-induced heart disease (RIHD) and radiation-induced vascular disease (RIVD). Symptoms are dose dependent and include cardiomyopathy, myocardial fibrosis, valvular heart disease, coronary artery disease, heart arrhythmia and peripheral artery disease. Radiation-induced fibrosis, vascular cell damage and oxidative stress can lead to these and other late side effect symptoms. Most radiation-induced cardiovascular diseases occur 10 or more years post treatment, making causality determinations more difficult.

 

Cognitive decline

In cases of radiation applied to the head radiation therapy may cause cognitive decline. Cognitive decline was especially apparent in young children, between the ages of 5 to 11. Studies found, for example, that the IQ of 5-year-old children declined each year after treatment by several IQ points.

 

Radiation enteropathy

The gastrointestinal tract can be damaged following abdominal and pelvic radiotherapy. Atrophy, fibrosis and vascular changes produce malabsorption, diarrhea, steatorrhea and bleeding with bile acid diarrhea and vitamin B12 malabsorption commonly found due to ileal involvement. Pelvic radiation disease includes radiation proctitis, producing bleeding, diarrhoea and urgency, and can also cause radiation cystitis when the bladder is affected.

 

Radiation-induced polyneuropathy

Radiation treatments are vitally necessary but may damage nerves near the target area or within the delivery path as nerve tissue is also radiosensitive. Nerve damage from ionizing radiation occurs in phases, the initial phase from microvascular injury, capillary damage and nerve demyelination. Subsequent damage occurs from vascular constriction and nerve compression due to uncontrolled fibrous tissue growth caused by radiation. Radiation-induced polyneuropathy, ICD-10-CM Code G62.82, occurs in approximately 1-5% of those receiving radiation therapy.

Depending upon the irradiated zone, late effect neuropathy may occur in either the central nervous system (CNS) or the peripheral nervous system (PNS). In the CNS for example, cranial nerve injury typically presents as a visual acuity loss 1-14 years post treatment.^[31] In the PNS, injury to the plexus nerves presents as radiation-induced brachial plexopathy or radiation-induced lumbosacral plexopathy appearing up to 3 decades post treatment.

Cumulative side effects

Cumulative effects from this process should not be confused with long-term effects—when short-term effects have disappeared and long-term effects are subclinical, reirradiation can still be problematic. These doses are calculated by the radiation oncologist and many factors are taken into account before the subsequent radiation takes place.

Effects on reproduction

During the first two weeks after fertilization, radiation therapy is lethal but not teratogenic. High doses of radiation during pregnancy induce anomalies, impaired growth and intellectual disability, and there may be an increased risk of childhood leukemia and other tumours in the offspring.

In males previously having undergone radiotherapy, there appears to be no increase in genetic defects or congenital malformations in their children conceived after therapy. However, the use of assisted reproductive technologies and micromanipulation techniques might increase this risk.

Effects on pituitary system

Hypopituitarism commonly develops after radiation therapy for sellar and parasellar neoplasms, extrasellar brain tumours, head and neck tumours, and following whole body irradiation for systemic malignancies. Radiation-induced hypopituitarism mainly affects growth hormone and gonadal hormones. In contrast, adrenocorticotrophic hormone (ACTH) and thyroid stimulating hormone (TSH) deficiencies are the least common among people with radiation-induced hypopituitarism. Changes in prolactin-secretion is usually mild, and vasopressin deficiency appears to be very rare as a consequence of radiation.

Radiation therapy accidents

There are rigorous procedures in place to minimise the risk of accidental overexposure of radiation therapy to patients. However, mistakes do occasionally occur; for example, the radiation therapy machine Therac-25 was responsible for at least six accidents between 1985 and 1987, where patients were given up to one hundred times the intended dose; two people were killed directly by the radiation overdoses. From 2005 to 2010, a hospital in Missouri overexposed 76 patients (most with brain cancer) during a five-year period because new radiation equipment had been set up incorrectly.

Although medical errors are exceptionally rare, radiation oncologists, medical physicists and other members of the radiation therapy treatment team are working to eliminate them. ASTRO has launched a safety initiative called Target Safely that, among other things, aims to record errors nationwide so that doctors can learn from each and every mistake and prevent them from happening. ASTRO also publishes a list of questions for patients to ask their doctors about radiation safety to ensure every treatment is as safe as possible.

Use in non-cancerous diseases

The beam's eye view of the radiotherapy portal on the hand's surface with the lead shield cut-out placed in the machine's gantry

 

Radiation therapy is used to treat early stage Dupuytren's disease and Ledderhose disease. When Dupuytren's disease is at the nodules and cords stage or fingers are at a minimal deformation stage of less than 10 degrees, then radiation therapy is used to prevent further progress of the disease. Radiation therapy is also used post surgery in some cases to prevent the disease continuing to progress. Low doses of radiation are used typically three gray of radiation for five days, with a break of three months followed by another phase of three gray of radiation for five days.

Technique

Mechanism of action

Radiation therapy works by damaging the DNA of cancerous cells. This DNA damage is caused by one of two types of energy, photon or charged particle. This damage is either direct or indirect ionization of the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA.

In photon therapy, most of the radiation effect is through free radicals. Cells have mechanisms for repairing single-strand DNA damage and double-stranded DNA damage. However, double-stranded DNA breaks are much more difficult to repair, and can lead to dramatic chromosomal abnormalities and genetic deletions. Targeting double-stranded breaks increases the probability that cells will undergo cell death. Cancer cells are generally less differentiated and more stem cell-like; they reproduce more than most healthy differentiated cells, and have a diminished ability to repair sub-lethal damage. Single-strand DNA damage is then passed on through cell division; damage to the cancer cells' DNA accumulates, causing them to die or reproduce more slowly.

One of the major limitations of photon radiation therapy is that the cells of solid tumors become deficient in oxygen. Solid tumors can outgrow their blood supply, causing a low-oxygen state known as hypoxia. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. Much research has been devoted to overcoming hypoxia including the use of high pressure oxygen tanks, hyperthermia therapy (heat therapy which dilates blood vessels to the tumor site), blood substitutes that carry increased oxygen, hypoxic cell radiosensitizer drugs such as misonidazole and metronidazole, and hypoxic cytotoxins (tissue poisons), such as tirapazamine. Newer research approaches are currently being studied, including preclinical and clinical investigations into the use of an oxygen diffusion-enhancing compound such as trans sodium crocetinate (TSC) as a radiosensitizer.

Charged particles such as protons and boron, carbon, and neon ions can cause direct damage to cancer cell DNA through high-LET (linear energy transfer) and have an antitumor effect independent of tumor oxygen supply because these particles act mostly via direct energy transfer usually causing double-stranded DNA breaks. Due to their relatively large mass, protons and other charged particles have little lateral side scatter in the tissue—the beam does not broaden much, stays focused on the tumor shape, and delivers small dose side-effects to surrounding tissue. They also more precisely target the tumor using the Bragg peak effect. See proton therapy for a good example of the different effects of intensity-modulated radiation therapy (IMRT) vs. charged particle therapy. This procedure reduces damage to healthy tissue between the charged particle radiation source and the tumor and sets a finite range for tissue damage after the tumor has been reached. In contrast, IMRT's use of uncharged particles causes its energy to damage healthy cells when it exits the body. This exiting damage is not therapeutic, can increase treatment side effects, and increases the probability of secondary cancer induction. This difference is very important in cases where the close proximity of other organs makes any stray ionization very damaging (example: head and neck cancers). This x-ray exposure is especially bad for children, due to their growing bodies, and they have a 30% chance of a second malignancy after 5 years post initial RT.

Dose

The amount of radiation used in photon radiation therapy is measured in grays (Gy), and varies depending on the type and stage of cancer being treated. For curative cases, the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy.

Preventive (adjuvant) doses are typically around 45–60 Gy in 1.8–2 Gy fractions (for breast, head, and neck cancers.) Many other factors are considered by radiation oncologists when selecting a dose, including whether the patient is receiving chemotherapy, patient comorbidities, whether radiation therapy is being administered before or after surgery, and the degree of success of surgery.

Delivery parameters of a prescribed dose are determined during treatment planning (part of dosimetry). Treatment planning is generally performed on dedicated computers using specialized treatment planning software. Depending on the radiation delivery method, several angles or sources may be used to sum to the total necessary dose. The planner will try to design a plan that delivers a uniform prescription dose to the tumor and minimizes dose to surrounding healthy tissues.

In radiation therapy, three-dimensional dose distributions may be evaluated using the dosimetry technique known as gel dosimetry.

Fractionation

This section only applies to photon radiotherapy although other types of radiation therapy may be fractionated

 

The total dose is fractionated (spread out over time) for several important reasons. Fractionation allows normal cells time to recover, while tumor cells are generally less efficient in repair between fractions. Fractionation also allows tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given. Similarly, tumor cells that were chronically or acutely hypoxic (and therefore more radioresistant) may reoxygenate between fractions, improving the tumor cell kill.

Fractionation regimens are individualised between different radiation therapy centers and even between individual doctors. In North America, Australia, and Europe, the typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week. In some cancer types, prolongation of the fraction schedule over too long can allow for the tumor to begin repopulating, and for these tumor types, including head-and-neck and cervical squamous cell cancers, radiation treatment is preferably completed within a certain amount of time. For children, a typical fraction size may be 1.5 to 1.8 Gy per day, as smaller fraction sizes are associated with reduced incidence and severity of late-onset side effects in normal tissues.

In some cases, two fractions per day are used near the end of a course of treatment. This schedule, known as a concomitant boost regimen or hyperfractionation, is used on tumors that regenerate more quickly when they are smaller. In particular, tumors in the head-and-neck demonstrate this behavior.

Patients receiving palliative radiation to treat uncomplicated painful bone metastasis should not receive more than a single fraction of radiation. A single treatment gives comparable pain relief and morbidity outcomes to multiple-fraction treatments, and for patients with limited life expectancy, a single treatment is best to improve patient comfort.

Schedules for fractionation

One fractionation schedule that is increasingly being used and continues to be studied is hypofractionation. This is a radiation treatment in which the total dose of radiation is divided into large doses. Typical doses vary significantly by cancer type, from 2.2 Gy/fraction to 20 Gy/fraction, the latter being typical of stereotactic treatments (stereotactic ablative body radiotherapy, or SABR – also known as SBRT, or stereotactic body radiotherapy) for subcranial lesions, or SRS (stereotactic radiosurgery) for intracranial lesions. The rationale of hypofractionation is to reduce the probability of local recurrence by denying clonogenic cells the time they require to reproduce and also to exploit the radiosensitivity of some tumors. In particular, stereotactic treatments are intended to destroy clonogenic cells by a process of ablation – i.e. the delivery of a dose intended to destroy clonogenic cells directly, rather than to interrupt the process of clonogenic cell division repeatedly (apoptosis), as in routine radiotherapy. 

Estimation of dose based on target sensitivity

Different cancer types have different radiation sensitivity. However, predicting the sensitivity based on genomic or proteomic analyses of biopsy samples has proved difficult. An alternative approach to genomics and proteomics was offered by the discovery that radiation protection in microbes is offered by non-enzymatic complexes of manganese and small organic metabolites. The content and variation of manganese (measurable by electron paramagnetic resonance) were found to be good predictors of radiosensitivity, and this finding extends also to human cells. An association was confirmed between total cellular manganese contents and their variation, and clinically-inferred radioresponsiveness in different tumor cells, a finding that may be useful for more precise radiodosages and improved treatment of cancer patients.

Types

Historically, the three main divisions of radiation therapy are :

• external beam radiation therapy (EBRT or XRT) or teletherapy;
• brachytherapy or sealed source radiation therapy; and
• systemic radioisotope therapy or unsealed source radiotherapy.

The differences relate to the position of the radiation source; external is outside the body, brachytherapy uses sealed radioactive sources placed precisely in the area under treatment, and systemic radioisotopes are given by infusion or oral ingestion. Brachytherapy can use temporary or permanent placement of radioactive sources. The temporary sources are usually placed by a technique called afterloading. In afterloading a hollow tube or applicator is placed surgically in the organ to be treated, and the sources are loaded into the applicator after the applicator is implanted. This minimizes radiation exposure to health care personnel. 

Particle therapy is a special case of external beam radiation therapy where the particles are protons or heavier ions. 

External beam radiation therapy

The following three sections refer to treatment using x-rays. 

Conventional external beam radiation therapy

A teletherapy radiation capsule composed of the following:

1. an international standard source holder (usually lead),
2. a retaining ring, and
3. a teletherapy "source" composed of
4. two nested stainless steel canisters welded to
5. two stainless steel lids surrounding
6. a protective internal shield (usually uranium metal or a tungsten alloy) and
7. a cylinder of radioactive source material, often but not always cobalt-60. The diameter of the "source" is 30 mm.

Historically conventional external beam radiation therapy (2DXRT) was delivered via two-dimensional beams using kilovoltage therapy x-ray units or medical linear accelerators which generate high energy x-rays. 2DXRT mainly consists of a single beam of radiation delivered to the patient from several directions: often front or back, and both sides.

Conventional refers to the way the treatment is planned or simulated on a specially calibrated diagnostic x-ray machine known as a simulator because it recreates the linear accelerator actions (or sometimes by eye), and to the usually well-established arrangements of the radiation beams to achieve a desired plan. The aim of simulation is to accurately target or localize the volume which is to be treated. This technique is well established and is generally quick and reliable. The worry is that some high-dose treatments may be limited by the radiation toxicity capacity of healthy tissues which lie close to the target tumor volume.

An example of this problem is seen in radiation of the prostate gland, where the sensitivity of the adjacent rectum limited the dose which could be safely prescribed using 2DXRT planning to such an extent that tumor control may not be easily achievable. Prior to the invention of the CT, physicians and physicists had limited knowledge about the true radiation dosage delivered to both cancerous and healthy tissue. For this reason, 3-dimensional conformal radiation therapy has become the standard treatment for almost all tumor sites. More recently other forms of imaging are used including MRI, PET, SPECT and Ultrasound.

Stereotactic radiation

Stereotactic radiation is a specialized type of external beam radiation therapy. It uses focused radiation beams targeting a well-defined tumor using extremely detailed imaging scans. Radiation oncologists perform stereotactic treatments, often with the help of a neurosurgeon for tumors in the brain or spine. 

There are two types of stereotactic radiation. Stereotactic radiosurgery (SRS) is when doctors use a single or several stereotactic radiation treatments of the brain or spine. Stereotactic body radiation therapy (SBRT) refers to one or several stereotactic radiation treatments with the body, such as the lungs.

Some doctors say an advantage to stereotactic treatments is that they deliver the right amount of radiation to the cancer in a shorter amount of time than traditional treatments, which can often take 6 to 11 weeks. Plus treatments are given with extreme accuracy, which should limit the effect of the radiation on healthy tissues. One problem with stereotactic treatments is that they are only suitable for certain small tumors.

Stereotactic treatments can be confusing because many hospitals call the treatments by the name of the manufacturer rather than calling it SRS or SBRT. Brand names for these treatments include Axesse, Cyberknife, Gamma Knife, Novalis, Primatom, Synergy, X-Knife, TomoTherapy, Trilogy and Truebeam. This list changes as equipment manufacturers continue to develop new, specialized technologies to treat cancers.

Virtual simulation, and 3-dimensional conformal radiation therapy

The planning of radiation therapy treatment has been revolutionized by the ability to delineate tumors and adjacent normal structures in three dimensions using specialized CT and/or MRI scanners and planning software.

Virtual simulation, the most basic form of planning, allows more accurate placement of radiation beams than is possible using conventional X-rays, where soft-tissue structures are often difficult to assess and normal tissues difficult to protect.

An enhancement of virtual simulation is 3-dimensional conformal radiation therapy (3DCRT), in which the profile of each radiation beam is shaped to fit the profile of the target from a beam's eye view (BEV) using a multileaf collimator (MLC) and a variable number of beams. When the treatment volume conforms to the shape of the tumor, the relative toxicity of radiation to the surrounding normal tissues is reduced, allowing a higher dose of radiation to be delivered to the tumor than conventional techniques would allow.

Intensity-modulated radiation therapy (IMRT)

Varian TruBeam Linear Accelerator, used for delivering IMRT

 

Intensity-modulated radiation therapy (IMRT) is an advanced type of high-precision radiation that is the next generation of 3DCRT. IMRT also improves the ability to conform the treatment volume to concave tumor shapes, for example when the tumor is wrapped around a vulnerable structure such as the spinal cord or a major organ or blood vessel. Computer-controlled x-ray accelerators distribute precise radiation doses to malignant tumors or specific areas within the tumor. The pattern of radiation delivery is determined using highly tailored computing applications to perform optimization and treatment simulation (Treatment Planning). The radiation dose is consistent with the 3-D shape of the tumor by controlling, or modulating, the radiation beam's intensity. The radiation dose intensity is elevated near the gross tumor volume while radiation among the neighboring normal tissues is decreased or avoided completely. This results in better tumor targeting, lessened side effects, and improved treatment outcomes than even 3DCRT.

3DCRT is still used extensively for many body sites but the use of IMRT is growing in more complicated body sites such as CNS, head and neck, prostate, breast, and lung. Unfortunately, IMRT is limited by its need for additional time from experienced medical personnel. This is because physicians must manually delineate the tumors one CT image at a time through the entire disease site which can take much longer than 3DCRT preparation. Then, medical physicists and dosimetrists must be engaged to create a viable treatment plan. Also, the IMRT technology has only been used commercially since the late 1990s even at the most advanced cancer centers, so radiation oncologists who did not learn it as part of their residency programs must find additional sources of education before implementing IMRT.

Proof of improved survival benefit from either of these two techniques over conventional radiation therapy (2DXRT) is growing for many tumor sites, but the ability to reduce toxicity is generally accepted. This is particularly the case for head and neck cancers in a series of pivotal trials performed by Professor Christopher Nutting of the Royal Marsden Hospital. Both techniques enable dose escalation, potentially increasing usefulness. There has been some concern, particularly with IMRT, about increased exposure of normal tissue to radiation and the consequent potential for secondary malignancy. Overconfidence in the accuracy of imaging may increase the chance of missing lesions that are invisible on the planning scans (and therefore not included in the treatment plan) or that move between or during a treatment (for example, due to respiration or inadequate patient immobilization). New techniques are being developed to better control this uncertainty—for example, real-time imaging combined with real-time adjustment of the therapeutic beams. This new technology is called image-guided radiation therapy (IGRT) or four-dimensional radiation therapy.

Another technique is the real-time tracking and localization of one or more small implantable electric devices implanted inside or close to the tumor. There are various types of medical implantable devices that are used for this purpose. It can be a magnetic transponder which senses the magnetic field generated by several transmitting coils, and then transmits the measurements back to the positioning system to determine the location. The implantable device can also be a small wireless transmitter sending out an RF signal which then will be received by a sensor array and used for localization and real-time tracking of the tumor position.

A well-studied issue with IRMT is the "tongue and groove effect" which results in unwanted underdosing, due to irradiating through extended tongues and grooves of overlapping MLC (multileaf collimator) leaves. While solutions to this issue have been developed, which either reduce the TG effect to negligible amounts or remove it completely, they depend upon the method of IMRT being used and some of them carry costs of their own. Some texts distinguish "tongue and groove error" from "tongue or groove error", according as both or one side of the aperture is occluded.

Volumetric modulated arc therapy (VMAT)

Volumetric modulated arc therapy (VMAT) is a radiation technique introduced in 2007 which can achieve highly conformal dose distributions on target volume coverage and sparing of normal tissues. The specificity of this technique is to modify three parameters during the treatment. VMAT delivers radiation by rotating gantry (usually 360° rotating fields with one or more arcs), changing speed and shape of the beam with a multileaf collimator (MLC) ("sliding window" system of moving) and fluence output rate (dose rate) of the medical linear accelerator. VMAT has an advantage in patient treatment, compared with conventional static field intensity modulated radiotherapy (IMRT), of reduced radiation delivery times. Comparisons between VMAT and conventional IMRT for their sparing of healthy tissues and Organs at Risk (OAR) depends upon the cancer type. In the treatment of nasopharyngeal, oropharyngeal and hypopharyngeal carcinomas VMAT provides equivalent or better OAR protection. In the treatment of prostate cancer the OAR protection result is mixed with some studies favoring VMAT, others favoring IMRT.

Automated planning

Automated treatment planning has become an integrated part of radiotherapy treatment planning. There are in general two approaches of automated planning. 1) Knowledge based planning where the treatment planning system has a library of high quality plans, from which it can predict the target and OAR DVH. 2) The other approach is commonly called protocol based planning, where the treatment planning system tried to mimic an experienced treatment planner and through an iterative process evaluates the plan quality from on the basis of the protocol.

Particle therapy

In particle therapy (proton therapy being one example), energetic ionizing particles (protons or carbon ions) are directed at the target tumor. The dose increases while the particle penetrates the tissue, up to a maximum (the Bragg peak) that occurs near the end of the particle's range, and it then drops to (almost) zero. The advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue.

Auger therapy

Auger therapy (AT) makes use of a very high dose of ionizing radiation in situ that provides molecular modifications at an atomic scale. AT differs from conventional radiation therapy in several aspects; it neither relies upon radioactive nuclei to cause cellular radiation damage at a cellular dimension, nor engages multiple external pencil-beams from different directions to zero-in to deliver a dose to the targeted area with reduced dose outside the targeted tissue/organ locations. Instead, the in situ delivery of a very high dose at the molecular level using AT aims for in situ molecular modifications involving molecular breakages and molecular re-arrangements such as a change of stacking structures as well as cellular metabolic functions related to the said molecule structures.

Contact x-ray brachytherapy

Contact x-ray brachytherapy (also called "CXB", "electronic brachytherapy" or the "Papillon Technique") is a type of radiation therapy using kilovoltage X-rays applied close to the tumour to treat rectal cancer. The process involves inserting the x-ray tube through the anus into the rectum and placing it against the cancerous tissue, then high doses of X-rays are emitted directly into the tumor at two weekly intervals. It is typically used for treating early rectal cancer in patients who may not be candidates for surgery. A 2015 NICE review found the main side effect to be bleeding that occurred in about 38% of cases, and radiation-induced ulcer which occurred in 27% of cases.

Brachytherapy (sealed source radiotherapy)

A SAVI brachytherapy device

Brachytherapy is delivered by placing radiation source(s) inside or next to the area requiring treatment. Brachytherapy is commonly used as an effective treatment for cervical, prostate, breast, and skin cancer and can also be used to treat tumours in many other body sites.

In brachytherapy, radiation sources are precisely placed directly at the site of the cancerous tumour. This means that the irradiation only affects a very localized area – exposure to radiation of healthy tissues further away from the sources is reduced. These characteristics of brachytherapy provide advantages over external beam radiation therapy – the tumour can be treated with very high doses of localized radiation, whilst reducing the probability of unnecessary damage to surrounding healthy tissues. A course of brachytherapy can often be completed in less time than other radiation therapy techniques. This can help reduce the chance of surviving cancer cells dividing and growing in the intervals between each radiation therapy dose.

As one example of the localized nature of breast brachytherapy, the SAVI device delivers the radiation dose through multiple catheters, each of which can be individually controlled. This approach decreases the exposure of healthy tissue and resulting side effects, compared both to external beam radiation therapy and older methods of breast brachytherapy.

Unsealed source radiotherapy (systemic radioisotope therapy)

Systemic radioisotope therapy (RIT) is a form of targeted therapy. Targeting can be due to the chemical properties of the isotope such as radioiodine which is specifically absorbed by the thyroid gland a thousandfold better than other bodily organs. Targeting can also be achieved by attaching the radioisotope to another molecule or antibody to guide it to the target tissue. The radioisotopes are delivered through infusion (into the bloodstream) or ingestion. Examples are the infusion of metaiodobenzylguanidine (MIBG) to treat neuroblastoma, of oral iodine-131 to treat thyroid cancer or thyrotoxicosis, and of hormone-bound lutetium-177 and yttrium-90 to treat neuroendocrine tumors (peptide receptor radionuclide therapy).

Another example is the injection of radioactive yttrium-90 or holmium-166 microspheres into the hepatic artery to radioembolize liver tumors or liver metastases. These microspheres are used for the treatment approach known as selective internal radiation therapy. The microspheres are approximately 30 µm in diameter (about one-third of a human hair) and are delivered directly into the artery supplying blood to the tumors. These treatments begin by guiding a catheter up through the femoral artery in the leg, navigating to the desired target site and administering treatment. The blood feeding the tumor will carry the microspheres directly to the tumor enabling a more selective approach than traditional systemic chemotherapy. There are currently three different kinds of microspheres: SIR-Spheres, TheraSphere and QuiremSpheres. 

A major use of systemic radioisotope therapy is in the treatment of bone metastasis from cancer. The radioisotopes travel selectively to areas of damaged bone, and spare normal undamaged bone. Isotopes commonly used in the treatment of bone metastasis are radium-223, strontium-89 and samarium (¹⁵³Sm) lexidronam.

In 2002, the United States Food and Drug Administration (FDA) approved ibritumomab tiuxetan (Zevalin), which is an anti-CD20 monoclonal antibody conjugated to yttrium-90. In 2003, the FDA approved the tositumomab/iodine (¹³¹I) tositumomab regimen (Bexxar), which is a combination of an iodine-131 labelled and an unlabelled anti-CD20 monoclonal antibody. These medications were the first agents of what is known as radioimmunotherapy, and they were approved for the treatment of refractory non-Hodgkin's lymphoma. 

Intraoperative radiotherapy

Intraoperative radiation therapy (IORT) is applying therapeutic levels of radiation to a target area, such as a cancer tumor, while the area is exposed during surgery.

Rationale

The rationale for IORT is to deliver a high dose of radiation precisely to the targeted area with minimal exposure of surrounding tissues which are displaced or shielded during the IORT. Conventional radiation techniques such as external beam radiotherapy (EBRT) following surgical removal of the tumor have several drawbacks: The tumor bed where the highest dose should be applied is frequently missed due to the complex localization of the wound cavity even when modern radiotherapy planning is used. Additionally, the usual delay between the surgical removal of the tumor and EBRT may allow a repopulation of the tumor cells. These potentially harmful effects can be avoided by delivering the radiation more precisely to the targeted tissues leading to immediate sterilization of residual tumor cells. Another aspect is that wound fluid has a stimulating effect on tumor cells. IORT was found to inhibit the stimulating effects of wound fluid.

Deep inspiration breath-hold

Deep inspiration breath-hold (DIBH) is a method of delivering radiotherapy while limiting radiation exposure to the heart and lungs. It is used primarily for treating left-sided breast cancer. The technique involves a patient holding their breath during treatment. There are two basic methods of performing DIBH: free-breathing breath-hold and spirometry-monitored deep inspiration breath hold.

History

X-ray treatment of tuberculosis in 1910. Before the 1920s, the hazards of radiation were not understood, and it was used to treat a wide range of diseases.

Medicine has used radiation therapy as a treatment for cancer for more than 100 years, with its earliest roots traced from the discovery of x-rays in 1895 by Wilhelm Röntgen. Emil Grubbe of Chicago was possibly the first American physician to use x-rays to treat cancer, beginning in 1896.

The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of Nobel Prize–winning scientist Marie Curie (1867–1934), who discovered the radioactive elements polonium and radium in 1898. This began a new era in medical treatment and research. Through the 1920s the hazards of radiation exposure were not understood, and little protection was used. Radium was believed to have wide curative powers and radiotherapy was applied to many diseases.

Prior to World War 2, the only practical sources of radiation for radiotherapy were radium, its "emanation", radon gas, and the x-ray tube. External beam radiotherapy (teletherapy) began at the turn of the century with relatively low voltage (<150 a="" be="" beams="" body="" could="" energy="" found="" higher="" href="https://en.wikipedia.org/wiki/Orthovoltage_X-rays" inside="" it="" kv="" low="" machines.="" more="" nbsp="" penetrating="" reach="" required="" requiring="" superficial="" that="" the="" title="Orthovoltage X-rays" to="" treated="" tumors="" voltage="" voltages.="" was="" were="" while="" with="" x-ray="" x-rays="">Orthovoltage X-rays

, which used tube voltages of 200-500 kV, began to be used during the 1920s. To reach the most deeply buried tumors without exposing intervening skin and tissue to dangerous radiation doses required rays with energies of 1 MV or above, called "megavolt" radiation. Producing megavolt x-rays required voltages on the x-ray tube of 3 to 5 million volts, which required huge expensive installations. Megavoltage x-ray units were first built in the late 1930s but because of cost were limited to a few institutions. One of the first, installed at St. Bartholomew's hospital, London in 1937 and used until 1960, used a 30 foot long x-ray tube and weighed 10 tons. Radium produced megavolt gamma rays, but was extremely rare and expensive due to its low occurrence in ores. In 1937 the entire world supply of radium for radiotherapy was 50 grams, valued at £800,000, or $50 million in 2005 dollars. 

The invention of the nuclear reactor in the Manhattan Project during World War 2 made possible the production of artificial radioisotopes for radiotherapy. Cobalt therapy, teletherapy machines using megavolt gamma rays emitted by cobalt-60, a radioisotope produced by irradiating ordinary cobalt metal in a reactor, revolutionized the field between the 1950s and the early 1980s. Cobalt machines were relatively cheap, robust and simple to use, although due to its 5.27 year half-life the cobalt had to be replaced about every 5 years. 

Medical linear particle accelerators, developed since the 1940s, began replacing x-ray and cobalt units in the 1980s and these older therapies are now declining. The first medical linear accelerator was used at the Hammersmith Hospital in London in 1953. Linear accelerators can produce higher energies, have more collimated beams, and do not produce radioactive waste with its attendant disposal problems like radioisotope therapies. 

With Godfrey Hounsfield’s invention of computed tomography (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery. CT-based planning allows physicians to more accurately determine the dose distribution using axial tomographic images of the patient's anatomy. The advent of new imaging technologies, including magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has moved radiation therapy from 3-D conformal to intensity-modulated radiation therapy (IMRT) and to image-guided radiation therapy (IGRT) tomotherapy. These advances allowed radiation oncologists to better see and target tumors, which have resulted in better treatment outcomes, more organ preservation and fewer side effects.

While access to radiotherapy is improving globally, more than half of patients in low and middle income countries still do not have available access to the therapy as of 2017.