Introduction to radiation therapy (Proceedings)

Please be aware that these notes are not designed to be a complete reference. It is advisable to consult with an oncologist for current treatment recommendations prior to developing a therapeutic plan for your patient.

Radiation Therapy (RT)

Use of energy (photons) or energized particles (electrons, protons, neutrons) to kill cancer cells. In general, this is a localized form of therapy, but total or half-body radiation is possible and injectable radioactive isotopes can be administered systemically. Radiation therapy is now much more available to veterinary patients (see www.vetcancersociety.org for sites) and it is important for veterinarians to have a basic understanding of its applications, toxicities, and how surgical interventions influence the success of RT for a tumor and even whether RT is an option for treating a tumor.

Therapeutic Radiation is Ionizing Radiation

Energy sufficient to cause ejection of an orbital electron is administered, typically by an external beam radiation treatment unit. Ejection of the electron is the molecular event that causes the damage eventually resulting in cell death. Radiation therapy may be electromagnetic (photons, e.g. x-rays, gamma rays) or particles (e.g. electrons, protons, neutrons, others).

Atom in radiated tissue

A photon is a massless packet of energy. Therapeutic x-rays are produced by a linear accelerator that accelerates an electron to a target (just like diagnostic xrays, only with more energy). Gamma rays are produced by the decay of a radioactive substance (most commonly cobalt-60).

Mechanism of Cell Killing by Radiation Therapy

Radiation therapy kills cells by injuring DNA. Through direct and indirect damage by the ejected electrons resulting from ionization of tissue atoms by RT, single strand breaks, double strand breaks, and base alterations are created. The electrons do not lose all of their energy in one direct or indirect interaction and may go on to cause multiple lesions. DNA injury can result in programmed cell death (apoptosis) which may occur immediately or following more cell divisions. In addition, radiation therapy may sterilize cancer cells (so they can't proliferate) without killing them.

Cells are most sensitive when DNA is unwound and glutathione levels are low (G2 and M phase of cell cycle) and generally die when they divide (mitotic death). This means rapidly proliferating cells are more sensitive to RT, so, according to Gomperzian growth kinetics, microscopic disease is most sensitive to RT. The exception is lymphoma, which undergoes mitotic and intermitotic death with RT.

2/3 of cell killing by RT is indirect. This means that electrons scattered by radiation interact with water to produce high energy free radicals that damage DNA.

1/3 of cell killing by RT is direct. This means that electrons scattered by radiation damage DNA.

Radiation Cell Survival Curve

A given dose of radiation kills a fixed proportion of cells, resulting in exponential cell killing (straight line on a logarithmic scale) based on dose, except at low doses where there is a "shoulder". The shoulder is curved because at lower doses, the damage to the cells is sublethal so some cells can repair the damage (so fewer cells die). It is generally not possible to cure a tumor with one dose of radiation because the normal tissue late toxicity would be life-threatening. For this reason, the total radiation dose is divided into multiple smaller doses called fractions. With each additional dose of radiation therapy, a fixed proportion of cells is killed.

Radiation cell survival curves

Fractionation of Radiation Therapy Doses

The total radiation dose is administered in multiple smaller doses called fractions. Fractions are given a minimum of 6 hours apart. The absorbed dose of radiation is measured in units called Gray (Gy = J/kg). Fractionation of RT doses allows acute responding normal tissues time to heal and, most importantly decreases the risk of late side effects. The smaller the dose per fraction, the higher the total dose that can be delivered without causing serious late side effects.

4 R's of RT – describe what happens to normal cells and tumor cells after each radiation fraction.

1. Repair – Cells receiving sublethal doses repair damage to their DNA between fractions. Normal cells repair DNA damage faster than tumor cells. This helps prevent damage to normal cells, but some tumor cells will also be repaired, especially if there is a large amount of time between fractions.

2. Redistribution – Proliferating cells are more sensitive to radiation therapy, especially in G2 and M phase. Remaining proliferating cells will be in G1 and S phase and cycle into G2 and M, hopefully allowing them to be killed with the next fraction.

3. Reoxygenation – Radiation therapy requires oxygen to kill cells (for generation of free radicals). Tumors have longer diffusion distance and abnormal blood flow. Radiation kills oxygenated cells, allowing poorly oxygenated cells better access to blood flow and O2, making them more sensitive to RT.

4. Repopulation – Fractionated dosing allows normal tissues to recruit stem cells to proliferate to replace injured cells. Unfortunately, it also allows tumor cells to proliferate between fractions.

Importance of Oxygenation in Radiation Therapy

Oxygen is necessary for free radical formation and indirect injury to DNA. Hypoxic cells are 2-3 times more resistant to RT. Large tumors have abnormal blood supply (longer diffusion distance between vessels, abnormal flow, stagnant, collapsing vessels, etc.), so RT is less effective at treating bulky tumors. In addition, scars are relatively hypoxic, so tumor cells in scars may, to some degree, be protected.

Relative Radiation Responsiveness of Tumor Types

In general, discrete cell tumors are the most sensitive to RT, followed by epithelial tumors, then mesenchymal tumors.

Commonly Used Sources of Radiation Therapy

In veterinary medicine, external beam RT (a beam of energy or particles, teletherapy) is used most commonly. This form of RT is applied from a distance and the sources most commonly used are linear accelerators.

Linear Accelerator = Linac - electromagnetic waves accelerate electrons toward a target. If the electrons hit the target, an x-ray photon of 4-25 MV is generated. If the target is removed, an electron beam of 5-22 MeV is generated. For photons, the maximum dose is below the skin and the depth depends on the energy of beam. The dose distribution is homogenous and penetrates deeply. If the electron beam is used, the energy of particle radiation is rapidly distributed in the tissue so a high dose can be administered superficially, sparing deep tissues (for instance when radiating skin over the lateral thorax or abdomen so the heart and lungs or intestines, kidneys, and liver are not injured).

Cobalt-60 – This form of radiation therapy is being used less now that linear accelerators are more available. Generates megavoltage (1.25 MV) gamma ray photons from the decay of radioactive cobalt. This radiation is skin sparing, deposits the maximum dose 0.5 cm below the skin, provides homogenous dose distribution, and penetrates deeply. This type of radiation produces a large penumbra (area of dose fall off) at the edge of the collimated beam.

Strontium Plesiotherapy – This is localized superficial RT typically delivered as a single treatment. It treats a dime-sized field (multiple fields may be treated) and penetrates 2-3 mm. It is useful for small lesions on the eyelid, face, or planum (for ex. SCC or mast cell tumors in cats).

Types of Radiation Therapy Protocols (Intent)

DEFINITIVE RT PROTOCOLS – Used most commonly. The safest and most effective type of RT protocol. Definitive protocols treat the tumor with the intent of cure or long term control. Patients are treated M-F for 3.5-5 weeks with total doses of 48-60 Gy given in 2.5-4 Gy fractions. Definitive protocols result in better tumor control, more acute toxicity, and decreased risk of late toxicity.

PALLIATIVE RT PROTOCOLS – Used in situations where a poor prognosis is expected (e.g. distant metastasis is present) or if the patient's overall condition prohibits definitive therapy. Palliative protocols are used most often for pain relief or relief of obstruction. Many different treatment protocols exist. Examples include weekly treatments for 4 weeks, treatments on days 0,7,21, or treatments M-F for 1 week. Doses of 20-36 Gy in 4-10 Gy fractions are administered. Palliative protocols result in poorer tumor control, less acute toxicity, and increased risk of late toxicity.

Adverse Effects of Radiation Therapy

Any tumor could be cured if you could give a high enough dose of radiation. The problem is the injury to the surrounding normal tissue. Radiation morbidity is divided into 2 types: acute and late.

Acute Normal Tissue Toxicity – Affects rapidly dividing cells (renewing cell populations). Develops during the second half of radiation therapy and heals by about 1 month after completion of RT. Severity increases with higher total doses and shorter treatment durations (example: toxicity is worse if you give 48 Gy over 3 weeks than if you give 48 Gy over 4 weeks). These side effects heal. They are treated symptomatically with antinflammatory agents (prednisone or NSAID), antibiotics, pain medications (NSAID, tramadol, codeine), mouthwash, and topical agents.

Examples of tissues affected and the morbidity seen include:

Skin – erythema, inflammation, dry desquamation, moist desquamation – this is not a "burn", it is the underlying stem cells that are injured (similar to the bone marrow and gi tract with chemotherapy)

Eye – keratitis, conjunctivitis, corneal ulcer

Mucosa (mouth, anus) – erythema, inflammation, mucositis, slough

Bone marrow – neutropenia, thrombocytopenia

Late Normal Tissue Toxicity – limits the total dose of RT that can be administered to a tumor because it does not heal and can be life-threatening. Non-renewing cell populations are affected (connective tissue, blood vessels, nerve, muscle, bone). Some late toxicities are expected, but life-threatening effects should be avoided. Late effects do not occur until at least 6 months after RT (usually >1 year) and definitive RT protocols are designed to reduce the risk of these effects to <5%. The likelihood of late RT effects increases with increasing dose per fraction and increasing total dose.

Examples of tissues affected and the morbidity seen include:

Skin – alopecia, hyperpigmentation, leukotrichia, ulceration, necrosis

Eye – decreased/absent tear production, cataract, retinal degeneration

Nerve/CNS – brain or spine necrosis

Bone – necrosis

Colon – chronic colitis/stricture

In addition, rarely 2nd tumors can occur in the RT field. These are usually sarcomas and occur an average of 5-6 years post RT.

Planning for Radiation Therapy

Radiation therapy is effective for local control of incompletely excised tumors. It is important to realize that if you do not completely remove a tumor, the entire surgical bed plus a margin of normal tissue around it must be radiated. It is possible for a surgeon to perform surgery that will prohibit a patient from being treated with RT. Surgical scar orientation should be planned with consideration of follow-up RT. For example, we should avoid spiraling an incision around a leg because a strip of skin must be spared from RT or lymphatic damage will result in distal limb edema. It is best to avoid placing drains through a tumor bed that exit at a distant site because the entire drain tract is contaminated with tumor cells. Incisions that "horseshoe" up one side, over the dorsum, and down the other side of the patient can create a RT field that is difficult or impossible to configure. Bottom line, if you are resecting an invasive tumor and incomplete excision is a possibility, you should consider consultation with an oncologist about scar orientation. Also, it is helpful if you place hemoclips at the extent of your surgical field. This will help the radiation oncologist identify the area to target with RT. Aggressive tumors or tumors in difficult locations may require advanced imaging (CT scan or MRI) to plan surgery and RT prior to the first resection.

Timing of Radiation Therapy and Surgery

RT may be performed before or after resection of a tumor. RT is most effective in the setting of microscopic disease. If performed before surgery, the main goal is to kill microscopic disease around the bulky tumor. Some tumors will shrink with radiation therapy. In general, most tumors are radiated post-operatively if incompletely excised. The exception is injection site sarcomas in cats, which are often radiated pre-operatively because of the small size of the cat, large size of the RT field (especially post-operatively), and risk of injury to normal tissues like spinal cord, lung, and kidney. At this time, there is no evidence to suggest that one order is better than another. Advantages and disadvantages of each include:

Applications of radiation therapy in veterinary patients