RADIOTHERAPY

RADIOTHERAPY

Radiation therapy [Radiation Oncology / Radiotherapy] sometimes abbreviated to XRT, is the medical use of ionizing radiation as part of cancer treatment to control malignant cells (not to be confused with radiology, the use of radiation in medical imaging and diagnosis).

Radiotherapy may be used for curative or adjuvant treatment. It is 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).

Total body irradiation (TBI) is a radiotherapy technique used to prepare the body to receive a bone marrow transplant.

Radiotherapy has several applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, prevention of keloid scar growth, and prevention of heterotopic ossification.

Radiotherapy is used for the treatment of malignant cancer, and may be used as a primary or adjuvant modality. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy, Immunotherapy or some mixture of the four.

Most common cancer types can be treated with radiotherapy 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.

Radiation therapy is commonly applied to the cancerous tumor. 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.

To spare normal tissues (such as skin or organs which radiation must pass through in order 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.

Brachytherapy, in which a radiation 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.

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 ionizing 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 the older, most common form of radiation therapy, Intensity-modulated radiotherapy (IMRT) (photons), most of the radiation effect is through free radicals. Because cells have mechanisms for repairing single-strand DNA damage, double-stranded DNA breaks prove to be the most significant technique to cause cell death.

Direct damage to cancer cell DNA occurs through high-LET (linear energy transfer) charged particles such as proton, boron, carbon or neon ions which have an antitumor effect which is independent of tumor oxygen supply because these particles act mostly via direct energy transfer usually causing double-stranded DNA breaks.

DOSE

The amount of radiation used in photon radiation therapy is measured in gray (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.

Preventative (adjuvant) doses are typically around 45 - 60 Gy in 1.8 - 2 Gy fractions (for Breast, Head, and Neck cancers.)

FRACTIONATION

This only applies to photon RT.

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.

EFFECT ON DIFFERENT TYPES OF CANCER

Different cancers respond differently to radiation therapy.

The response of a cancer to radiation is described by its radiosensitivity.

Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation.

Examples: Leukemias, most Lymphomas and Germ cell tumors.

The majority of epithelial cancers are only moderately radiosensitive, and require a significantly higher dose of radiation (60-70Gy) 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.

Examples: Renal cell cancer and melanoma are generally considered to be radioresistant.

TYPES OF RADIATION THERAPY

Historically, the three main divisions of radiotherapy are

1)     External Beam Radiotherapy (EBRT / XRT / Teletherapy)

2)     Brachytherapy (Sealed Source Radiotherapy)

3)     Systemic Radioisotope Therapy (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.

EXTERNAL BEAM RADIOTHERAPY

External Beam Radiotherapy [Teletherapy] is the most frequently used form of radiotherapy. The patient sits or lies on a couch and an external source of radiation is pointed at a particular part of the body.

In contrast to internal radiotherapy (brachytherapy), in which the radiation source is placed inside the body, external beam radiotherapy directs the radiation at the tumour from outside the body.

Kilovoltage (also known as superficial) x-rays are used for treating skin cancer and superficial structures.

Megavoltage (or deep) x-rays are used to treat deep-seated tumours (e.g. bladder, bowel, prostate, lung, brain).

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

CONVENTIONAL EXTERNAL BEAM RADIOTHERAPY

Conventional external beam radiotherapy (2DXRT) is delivered via two-dimensional beams using linear accelerator machines.

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 lay 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 radiotherapy is becoming the standard treatment for a number of tumor sites.

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 are they deliver the right amount of radiation to the cancer in a shorter amount of time than traditional treatments, which can often take six 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 and Trilogy.

VIRTUAL SIMULATION

The planning of radiotherapy 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.

3-DIMENSIONAL CONFORMAL RADIOTHERAPY

An enhancement of virtual simulation is 3-Dimensional Conformal Radiotherapy (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 RADIOTHERAPY

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 tissue is decreased or avoided completely.

The customized radiation dose is intended to maximize tumor dose while simultaneously protecting the surrounding normal tissue. This may result in better tumor targeting, lessened side effects, and improved treatment outcomes than even 3DCRT.

PARTICLE THERAPY

In particle therapy (Proton therapy), 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.

BRACHYTHERAPY

Brachytherapy (internal radiotherapy) 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.

As with stereotactic radiation, brachytherapy treatments are often known by their brand names.

Brand Names: For breast cancer brachytherapy treatments include SAVI, MammoSite, and Contura.

Brand Names: For prostate cancer include Proxcelan, TheraSeed, and I-Seed.

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 radiotherapy - 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 radiotherapy techniques. This can help reduce the chance of surviving cancer cells dividing and growing in the intervals between each radiotherapy 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 radiotherapy and older methods of breast brachytherapy.

RADIOISOTOPE THERAPY (RIT)

Systemic radioisotope therapy 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.

Example 1: 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).

Example 2: The injection of radioactive glass or resin microspheres into the hepatic artery to radioembolize liver tumors or liver metastases.

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 strontium-89 and samarium (153Sm) lexidronam.

SIDE EFFECTS

Radiation therapy is in itself painless. Many low-dose palliative treatments (for example, radiotherapy 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 edema compressing nerves in the treated area.

Treatment to higher doses causes varying side effects during treatment (acute side effects), in the months or years following treatment (long-term 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. One of the aims of modern radiotherapy is to reduce side effects to a minimum, and to help the patient to understand and to deal with those side effects which 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 skin irritation will also go away, but it may not be as elastic as it was before.

ACUTE SIDE EFFECTS

§  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.

Ø  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 radiotherapy, and the skin may break down.

Ø  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.

Ø  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.

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

§  Swelling (edema or edema): As part of the general inflammation that occurs, swelling of soft tissues may cause problems during radiotherapy.

Ø  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).

Ø  Surgical intervention may be considered prior to treatment with radiation. If surgery is deemed unnecessary or inappropriate, the patient may receive steroids during radiotherapy 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.

Ø  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.

Ø  Fibrosis

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

Ø  Epilation (Hair Loss)

§  Epilation 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.

Ø  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.

Ø  Lymphedema

§  Lymphedema, a condition of localized fluid retention and tissue swelling, can result from damage to the lymphatic system sustained during radiotherapy. It is the most commonly reported complication in breast radiotherapy patients.[31]

Ø  Cancer

§  Radiation is a potential cause of cancer, and secondary malignancies are seen in a very small minority of patients - usually less than 1/1000. It usually occurs 20 - 30 years following treatment, although some haematological malignancies may develop within 5 - 10 years. In the vast majority of cases, this risk is greatly outweighed by the reduction in risk conferred by treating the primary cancer. The cancer occurs within the treated area of the patient.

Ø  Heart disease

§  Radiation has potentially excess risk of death from heart disease seen after some past breast cancer RT regimens.[32]

Ø  Cognitive decline

§  In cases of radiation applied to the head radiation therapy may cause cognitive decline.

Ø  Radiation Proctitis

§  This can involve long-term effects on the rectum including bleeding, diarrhoea and urgency and is associated with radiotherapy to pelvic organs. Pelvic radiotherapy can also cause radiation cystitis when the bladder is affected.