INTRODUCTION TO RADIATION ONCOLOGY
Greg Almond, DVM, DACVR
Auburn University College of Veterinary Medicine
Radiation oncology is the discipline dealing with the treatment of disease (predominately
neoplasia) using ionizing radiation. Associated terms include radiation therapy, radiotherapy and
therapeutic irradiation.
Radiation therapy is generally not practical or economically feasible in general veterinary
practices because of expensive equipment and special licensing requirements. Radiation
oncology services are increasingly available at university veterinary hospitals and specialty
practices throughout the United States.
Primary treatment options for neoplastic diseases include surgery, chemotherapy and radiation
therapy. Other options include hyperthermia, immunology, phototherapy and others. Frequently,
a combination of treatment modes offers the best chance for cure or control of tumors. Surgery,
chemotherapy and radiation are commonly used in various combinations in veterinary oncology.
Indications for radiation therapy include treatment of:
Highly radiosensitive tumors
Nonresectable tumors
Incompletely resected tumors
Recurrent tumors or those likely to recur
Palliation of advanced tumors
Radiation therapy is based on principles of radiation physics and radiobiology.
RADIATION PHYSICS
Types of radiation commonly used in veterinary radiotherapy
Particulate (electrons, beta particles) - have mass and charge
Photons (x-rays, gamma rays) - have no mass, no charge
Because of their mass in charge, particulate radiations have a high probability of interaction in
tissue and therefore tend to deposit their energy more superficially and do not penetrate as deeply
as photons.
Because they have no mass or charge, photons have lower probability of interaction with tissue
and tend to penetrate more deeply.
At energies used for radiation therapy, both photons (x-rays and gamma rays) and particulate
radiations (electrons – also known as beta particles) cause ionization by ejecting electrons from
atoms/molecules in tissue.
The critical ionization target that results in cell death is DNA molecules in chromosomes within
cellular nuclei.
Radiation dose (absorbed in tissue) is measured in the international unit: Gray (Gy).
1 Gy = 1 coulomb/kilogram
1 Gray (Gy) = 100 Centigray (cGy) = 100 rads
1 Centigray (cGy) = 1 rad
Therapeutic radiation can be delivered from a variety of sources. The delivery of radiation for
treatment of tumors is usually divided into two categories: teletherapy and brachytherapy.
In teletherapy the radiation source is at some distance from the patient and a radiation
beam is directed at the treatment site. The radiation source is not in contact with the patient or
tumor. Also known as external beam radiation therapy (EBRT). Several types of machines are
used for teletherapy:
Superficial x-ray therapy machines (150 kV)
Orthovoltage x-ray therapy machines (200-500 kV) and
Cobalt-60 radiation therapy units (1.25 MeV gamma rays)
Clinical linear accelerators (4 – 23 MV x-rays and 4-15 MeV electrons)
Superficial x-ray therapy machines and orthovoltage units were in common use for treatments of
human patients in the 1930s -1960s and are still used by some veterinary oncologists today. The
superficial machines were designed for use by dermatologists and are only effective for skin
tumors. Orthovoltage x-ray machines were the first general-purpose radiation therapy machines.
Because of their relatively low radiation energy (compared to megavoltage units), they cause
more secondary reaction to the skin and are less effective for deep tumors. They can be used
effectively for treating cutaneous and subcutaneous tumors and tumors that are not deep in tissue.
Megavoltage x-ray therapy units (cobalt-60 and linear accelerators) and are the current state-ofthe-art for radiation oncology. Megavoltage simply means that the radiations produced carry
greater than one million electron volts of energy. Megavoltage photon beams offer three primary
advantages over lower energy orthovoltage beams
Greater penetration allowing deeper and more uniform dose distribution
Skin sparing (lower dose at skin surface than just below skin) - maximum
dose is at 0.5cm with Co-60 and at 1.5cm with a 6MV linear accelerator
Less preferential absorption by bone
All three factors improve the response to radiation therapy by allowing greater dose to the tumor
and less dose to surrounding normal tissues. The skin sparing reduces the incidence of radiation
dermatitis, a common secondary effect. Reduced dose to bone lowers the probability of bone
necrosis and avoids bone “blocking” radiation from tumor cells adjacent to bone.
Some accelerators can also produce therapeutic electron beams. Because of higher probability of
interaction with tissue, electrons deposit their energy more superficially, and do not penetrate
deeply. This property can be used to great advantage when treating tumors of the thoracic or
abdominal wall where deep penetration would cause unacceptable damage to internal organs.
With electron beams, a therapeutic radiation dose can be delivered to the thickness of the body
wall, with minimal dose to deeper tissues. This provides significant advantage in treating vaccine
associated sarcomas in cats and other superficial tumors in animals where it is important to spare
vital tissues deep to the tumor.
In brachytherapy the radiation source is placed within the tumor (interstitial therapy) or
on the surface of the tumor (plesiotherapy). Sources most commonly used in veterinary
radiotherapy are:
Iridium-192 radioactive seeds for tumor implantation (interstitial therapy)
Strontium-90 beta probe (ophthalmic applicator) - very superficial tumors
Brachytherapy using sources noted above is employed at Auburn University but is available at
relatively few veterinary radiation oncology centers. Iridium-192 implants have been particularly
useful in treating equine sarcoids and other superficial tumors in horses. Strontium-90 treatment
is used most often for treatment of corneal/conjunctival ocular tumors after lamellar keratectomy
and also for small, very superficial tumors of this skin, oral cavity and nasal planum. The
effective penetration of strontium-90 beta particles is only 2mm.
RADIATION BIOLOGY / TUMOR RESPONSE
Radiation kills cells by ionization of molecules. The critical target is the DNA molecule within
the chromosomes.
Lethal damage to the cell may be caused by direct or indirect ionization of chromosomal DNA.
Direct ionization occurs when radiation is absorbed the DNA molecule itself. Indirect ionization
occurs when the radiation ionizes water molecules releasing highly reactive free radicals that are
able to diffuse to and damage the DNA molecules. The indirect mode is predominant with photon
and electrons radiation typically used in veterinary radiation treatments.
Intracellular mechanisms can repair some chromosome breaks, but if there are double strand
breaks or multiple breaks, the damage cannot be repaired and is lethal.
After receiving lethal radiation damage, a cell is rendered incapable of reproduction. The cell
does not die at the time of radiation, but dies when it attempts to undergo mitosis. The cell can
continue to live and function until it tries to divide, at which time the lethal chromosome damage
causes cell death
Ionizing radiation affects both normal cells and neoplastic cells. Tumor cells are not necessarily
more radiosensitive than surrounding normal tissue.
The primary determinants of radiosensitivity or radioresistance are mitotic activity (the rate of
cell division) and degree of cellular differentiation, as discovered by two French radiobiologists
and commonly known as the Law of Bergonie’ and Tribondeau. It states:
Radiosensitivity is directly related to mitotic activity and inversely related to cell
differentiation.
Cells that are rapidly dividing and poorly differentiated are the most radiosensitive while cells
that are slowly dividing and well differentiated are the most radioresistant. Tumor cells tend to
have radiosensitive properties, but their sensitivity is highly variable. Normal tissue such as bone
marrow and intestinal epithelium are highly radiosensitive. Skin and mucous membranes also
tend to be sensitive. It is not true that all tumor cells are more radiosensitive than normal cells.
The goal of effective radiation treatment is to do the most damage to the tumor and the least
damage to the surrounding normal tissues in the radiation field. Unfortunately, there is not a
wide separation between the sensitivity of tumors and normal tissues. If enough radiation is given
to assure eradication of the tumor, there is often a high probability of damage to surrounding
normal tissues. Because of this, there is a narrow line between effective tumor treatment and
unacceptable secondary effects. As a result, the limiting factor in the ability to completely
eradicate tumors is the response of associated normal tissues.
Through decades of trial and error in the early 1900s it was determined that tumors could be most
effectively treated by giving multiple small doses of radiation rather than a few large doses.
Administering external beam radiation in small doses on an every day or every other day
schedule is called fractionation. Each of the individual doses is called a fraction. The sum of the
fractions and is the total dose.
The reasons for the effectiveness of fractionated radiation treatment are complex, but have been
elucidated by experimental radiobiology in which cell cultures are irradiated in vitro and cell
survival curves determined. The major principles of fractionation are known as the "4 R’s of
Radiation Therapy”
Repair
Repopulation
Reoxygenation
Reassortment
They are extensively discussed in radiation biology texts, if you are interested.
The standard fractionation protocol for treatment of human patients is 2.0 Gy fractions five days a
week for six weeks (30 fractions) for a total dose of 60Gy.
Animal patients are treated every day (M-F) or every other day (M,W,F) for approximately 4
weeks with fractions of 3.0-4.0 Gy for total doses of 40–60 Gy. Palliative protocols involve
fewer fractions at 4- 10 Gy. (See fractionation chart at end of notes).
Curative vs. Palliative Radiation Treatment
Treatment aimed at eradication of all viable tumor cells or long-term remission of tumors is
described as being of curative intent. The fractionated protocols listed above are administered
with the treatment goal of achieving cure or long-term tumor remission. Because of the lifethreatening consequences of most neoplasms, some secondary effects are considered acceptable
when striving for long-term control or cure. More aggressive treatment is justified when there is
curative intent.
Palliative radiation therapy is designed for relief of discomfort and/or dysfunction in advanced
tumors where there is little chance of cure or long-term control. Palliative irradiation usually
involves only a few fractions with the goal of short-term relief of signs and symptoms, while
minimizing stress, secondary effects and expense. Palliative protocols are indicated for patients
with extensive disease, metastatic disease, and/or when other treatments have failed. The goal of
palliation is to improve quality of life for some weeks or months. Palliative radiation therapy is
not expected to achieve cure or long-term tumor control.
Surgery and Radiation Therapy
Surgery and radiation therapy are often used in combination. Radiation therapy may be
administered:
Post-operative
Pre-operative
Intra operative
Postoperative irradiation is most common and usually most effective. It offers the advantage of
reduced cell numbers, reduced tumor volume and definitive diagnosis provided by excisional
biopsy. Many tumors are operated with curative intent, but adjunctive radiation is offered when
histopathologic examination shows incomplete surgical margins. Postoperative irradiation can be
begun immediately after surgery, but is usually initiated 2-3 weeks after surgery to allow for
healing of the surgical wound.
Preoperative irradiation is employed in neoplasms known to be highly radiosensitive or in cases
where the tumor is in operable because of cosmetic or functional considerations. Preoperative
tumor can, in some cases, effect adequate reduction of the mass to allow excision and otherwise
in operable tumor.
Intraoperative irradiation is rarely used, but can be effective in delivering a therapeutic dose to
isolated internal organs or tissues during surgery.
Radiation Treatment Planning
Radiation therapy treatment planning is a complex process involving experience and clinical
judgment in evaluation of neoplastic disease combined with a working knowledge of radiation
biology and radiation therapy physics. Treatment planning is the essential work of a radiation
oncologist involving not only evaluation of the patient, but also dosimetry decisions that may
involve "hand calculations" using a portable calculator and/or more complex distribution of
radiation dose using a 2-D or 3-D computerized treatment planner. When radiation therapy
machines are commissioned, radiation physicists must be hired to calibrate the equipment.
Thousands of individual dosimetry measurements must be made and entered into tables as well as
the computerized treatment planners for use by the radiation oncologist in dosimetry calculations.
Considerations in a treatment plan include known tumor response and surrounding normal tissue
response to radiation, extent and stage of disease, palliative or curative intent, patient positioning,
sparing of critical organs or tissues, type and energy of radiation, tumor depth and location, field
size and shape, and fractionation scheme. Multiple beam combinations, beam blocks, wedges
and use of surface bolus material are other adaptations often to achieve best dose distribution.
CT or MRI images are essential for modern radiation therapy planning, especially when tumors
are deep, invasive or cannot be fully palpated. The cross-sectional images allow accurate
determination of the extent and margins of the tumor, facilitating selection of a radiation
treatment field that includes the entire tumor with appropriate margins while sparing as much
normal tissue as possible. The cross-sectional nature of the images allows visual assessment of
the most appropriate angle or angles to direct the radiation beam. CT and MRI also allow
accurate digital measurement (to 0.1 millimeter) for calculation of radiation dose.
Cross-sectional images are required for computerized radiation treatment planning in order to
enter patient contours as well as the location of the tumor and critical organs into the computer
program. The images may be digitized from film or imported directly into treatment planning
computers where the pixel values are used not only to identify structures but also to account for
density differences that affect radiation absorption throughout the patient. Even when diagnostic
scans have been performed earlier, an additional treatment planning scan may be necessary
because the patient must be positioned for the scan exactly as it will be positioned on the
radiation treatment table with appropriate external markers so that the relationship of organs and
the depths of specific points in tissue can be simulated for dose calculation.
Tumor Response
As noted above, tumor cells do not die at the time of the radiation but when they undergo mitosis.
For this reason, tumors regress at a variable rate after radiation therapy. Rapidly dividing tumors
will regress more rapidly but may also reoccur more rapidly if all cells are not eradicated.
Tumors with slowly dividing cells may not regress at all during the four weeks of radiation
therapy but slowly shrink over subsequent weeks or months. The rate of tumor regression is not
an accurate predictor of the success of treatment.
An exception to the rule of mitotic death is lymphocytes and lymphocytic tumors. Lymphocytic
cells exhibit interphase death after irradiation (apparently caused by accelerated apoptosis), and
as a result lymphoid tumors tend to regress very rapidly. Radiation can assist in emergency relief
of dyspnea and dysphagia in animals with large cranial mediastinal lymphomas and in relief of
paresis/paralysis in animals afflicted with spinal lymphoma.
Secondary Effects to Normal Tissue
There is no magic that allows radiation to kill neoplastic cells and not normal cells. To achieve
effective tumor control, some adverse normal tissue reactions are usually encountered. Most of
the secondary effects are transient, and not severe. It is also important to note that there is
considerable variation among individuals in response of normal tissue to irradiation. The same
radiation dose and protocol that causes troublesome secondary effects in one individual animal
may cause no secondary effects in another.
Most of the secondary effects encountered in veterinary radiotherapy are local rather than
systemic. Only the tissues in the radiation beam will be affected. Radiation sickness with
vomiting, diarrhea and other systemic signs often reported in humans occurs with irradiation of
internal organs. Tumors of internal organs are not often treated in veterinary medicine
Secondary effects of radiation therapy to normal and tissues are categorized as early (acute) or a
late (delayed) effects.
Early (acute) effects of radiation therapy:
Occur 24 hrs - 2 wks after treatment (usually begin 2nd or 3rd week of therapy)
Affect rapidly dividing tissues:
Skin – (erythema, epilation, dry desquamation, moist desquamation, ulceration)
Mucositis - (lips, gums, anus, other mucus membranes)
Ocular – (conjunctivitis, blepharitis)
Usually heal uneventfully within 2-3 weeks after treatment completed.
Management is symptomatic with particular attention to hygiene and prevention
of self trauma (scratching, licking, chewing, rubbing).
Late (delayed) effects of radiation therapy:
Occur months to years after completion of radiation therapy
Affect slowly dividing tissues:
Fibrosis or necrosis of skin or mucosa (loss of germinal cells)
Bone, brain, spinal cord necrosis
Pulmonary fibrosis
Cataractogenesis
Carcinogenesis (radiation induced tumors)
Very difficult/discouraging to treat - the limiting factor of radiotherapy success
Caused by large-dose fractions
Can be avoided by using low dose per fraction (i.e. more small fractions rather than fewer large
fractions)
External Beam Radiation Therapy
Fractionation Schedules
DAYS
#FRX
DOSE/FRX
DOSE
TIME
Definitive Treatment (curative or long term control)
M-F
30
2Gy
60Gy
6wk
(Standard human schedule to which all others are compared)
M-W-F
12
4Gy
48Gy
4wk
54-60Gy
3-4wk
(Older veterinary schedule)
M-F
16-19
2.5-3.5Gy
(Newer veterinary schedule)
M-F
22
2.2Gy
48.4Gy
4wk+
M-W-F
21
3Gy
63Gy
7wk
Palliative Treatment
Weekly
3-5
8Gy
24-40Gy
3-5wk
0-7-21
3
10Gy
30Gy
3 wk
Single
1
10Gy
10Gy
1 day
MWF/M-F
2-6
5-10Gy
10-36Gy
2day-2wk
Quad Shot
4
4Gy
16Gy
2 days
(2 fractions per day for 2 consecutive days - 6 hrs between fractions)
Different Methods of Delivering External Beam Radiation Therapy (EBRT):
1. Conventional radiation therapy-the radiation field is shaped as a square or rectangle. Lead
blocks can be placed on an acrylic tray close to the radiation source to provide crude shaping
of the field. Single or multiple beams are used directed at the target.
2. Conformal radiation therapy (3-D CRT)-linear accelerators equipped with multi-leaf
collimators (MLCs) are able to shape the radiation field more closely to the shape of the
tumor from any given angle. A MLC is analogous to a contour gauge, the tool a carpenter
uses a copy a shape of something for replication. Conforming to the shape of the tumor
reduces the amount of normal tissue dose received during therapy. Again single or multiple
beams are used.
3. Intensity Modulated Radiation Therapy (IMRT)-multiple radiation beams are
used all directed at the target. While the beam is turned on, the MLC’s move allowing
more dose to reach thicker parts and less dose to thinner parts. Because of this, the
desired dose conforms more tightly to the tumor it further reduces dose to
surrounding normal tissues than does 3-D CRT.
4. Stereotactic Radiosurgery (SRS)/Stereotactic Body Radiation Therapy (SBRT):
a. By definition SRS is a single dose given to the brain
b. SBRT is 1 to 5 doses delivered to anywhere else in the body
c. Simply put, SRS and SBRT are IMRT combined with advanced onboard
imaging ensuring a high degree of accuracy of patient positioning allowing
very few very high doses of radiation to be delivered.
d. As with IMRT, the dose is delivered from multiple beams. Newer linear
accelerators are capable of delivering what is called “arc therapy”, meaning
the gantry rotates around the patient in an arc while delivering radiation
instead of multiple discrete angles. During the rotation of the gantry, the
MLC’s are constantly moving, modulating the dose.
e. Because positioning is very precise, the dose conforms to the tumor much
tighter than with standard IMRT enabling a high dose to be delivered to the
tumor with doses below tolerance level to nearby normal tissues.
f. The obvious advantages to the patient are less anesthetic episodes and greater
sparing of normal tissues adjacent to the tumor.