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RADIATION INJURY
Traditionally believed that small vessel injury is the problem, but now known that this is a late manifestation.
The parenchymal fibroblast is the key cell in wound repair. It is depleted in radiation injury.
With time radiation atrophy leads to ulceration.
HISTORY
1875: Roentgen discovers X-rays.
1897: Freund treats a hairy mole with X-rays.
1898: Curries discover radioactivity.
IONIZING RADIATION AND ITS EFFECT ON TISSUES
 Absorption of radiation leads to excitation of tissue electrons or ionisation of the atoms or molecules.
 Ionising radiation is that which is of sufficient energy to eject one or more electrons from an atom or molecule.
 This results in the release of energy which inflicts significant localised damage to a cell. This interaction is
therapeutic if the cell is cancerous and detrimental if it is not.
 Damage may be lethal or sublethal – causing cells to function abnormally
TYPES OF IONIZING RADIATION
Either electromagnetic or particulate.
Electromagnetic
 Wavelength can vary: very short to very long (microwaves and radiowaves).
 Electromagnetic radiation further consists of discrete quanta of energy = photons.
 X-rays and  rays are high energy photons of very short wavelength(high frequency) that are capable of
producing ionising damage to human tissue.
 X-rays are produced in an electrical device (eg a linear accelerator).
 -rays are emitted from the unstable nuclei of radioactive substances called isotopes (eg radium, cobalt, etc).
 rays are electromagnetic waves or photons emitted from the nucleus (center) of an atom.
 X Rays are electromagnetic waves or photons not emitted from the nucleus, but normally emitted by energy
changes in electrons. These energy changes are either in electron orbital shells that surround an atom or in the
process of slowing down such as in an X-ray machine.
Particulate radiation
 Produced by particles: electrons, protons,  particles, neutrons, etc.
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 Usually charged.
 Capable of ionising any tissue they traverse (Which they do at high velocity).
 A beta is a high speed particle, identical to an electron, that is emitted from the nucleus of an atom
 An alpha is a particle emitted from the nucleus of an atom, that contains two protons and two neutrons. It is
identical to the nucleus of a Helium atom, without the electrons.
 Neutrons are neutral particles that are normally contained in the nucleus of all atoms and may be removed by
various interactions or processes like collision and fission
Ionisation of Tissues
 May be direct or indirect.
1. Direct ionisation occurs when radiation acts upon a critical target within a cell to cause resultant damage.
Targets are DNA, endoplasmic reticulum etc
2. Indirect ionisation acts through a series of highly reactive species: free radicals.
 Water and oxygen are important in free radical formation and can be used to modify the response to radiation.
Measurements
Gray (Gy)
 Measures absorbed dose.
 One gray is equal to one joule of energy deposited in one kg of a material.
 Does not describe the biological effects of the different radiations.
 Absorbed dose is often expressed in terms of hundredths of a gray, or centi-grays. One gray is equivalent to
100 rads.
Sievert (Sv)
 Measures equivalent dose.
 This relates the absorbed dose in human tissue to the effective biological damage of the radiation.
 Not all radiation has the same biological effect, even for the same amount of absorbed dose.
 Equivalent dose is often expressed in terms of millionths of a sievert, or micro-sievert.
 SV= absorbed dose (Gy) x quality factor (Q) that is unique to the type of incident radiation.
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DELIVERY OF RADIATION
 Interstitial, intracavity or placed directly on or in the tumour. These methods provide a high local dose to the
tumour. = Brachytherapy.
 External beam radiation = Teletherapy. Eg: -rays (cobalt, cesium), x-rays (linear accelerator), particulate
beams (protons, electrons). These beams differ markedly in quality and energy.
Beam Energy
 Depth of maximal radiation dose(Dmax) is determined by energy of radiation.
o Superficial irradiation(10-125keV)
o Orthovoltage (125-400keV) – largely historical, high risk of osteonecrosis
o Super/Mega voltage (>400keV) – for deep-seeded tumors. Most skin sparing
 Electrons good for superficial therapy
 Neutrons reserved for large, aggressive tumor burdens
Brachytherapy
Advantages
1) continuous dosing – reduction of overall treatment time
2) sparing of uninvolved tissue – radiation localised to 3cm of catheters
Plesiotherapy – treatment of superficial lesions with a mould containing radioactive material.
BIOLOGICAL ASPECTS OF THERAPEUTIC RADIATION
 Different cells and tissues have different susceptibility to radiation.
 Cells cycle in and out of phases of radiosensitivity and radioresistance.
 Cells are most sensitive to radiation in the G2-M phase and least sensitive in the late S phase of the cell cycle.
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 Fractioning the therapy aims at decreasing the dose to normal tissue while maximising tumour cell kill.
o Need to allow time for normal cells to heal but not cancer cells to repopulate
o Probability of injury to the early responding tissues (i.e. cancerous cells) is increased through a
decreased overall treatment time.
o In contrast, the most important factor affecting the risk of injuring late responding tissues has been
determined to be the actual individual fraction dose.
o Schedules
1) Hyperfractionation – 2 doses 6 hours apart. Lower total dose
2) Hypofractionation – palliation or treatment of melanoma. Higher total dose.
3) Accelerated fractionation – boost doses given. Same total dose
 Radiation damage may be classified into 3 categories:
1) Lethal damage  irreversible, irreparable, irrevocable
2) Sublethal damage Can be repaired given time, nutrients, etc.
3) Potentially lethal damagedamage that can be modified by changing the cell’s environment.
 Dose rate (Gy per minute) is proportional to cell killing.
 Oxygen is the factor that can most modify the effect of ionising radiation.
 Cells are 2-3 times more sensitive to radiation in the presence of oxygen than in an anoxic environment.
 Tolerance Dose (TD) is the dose that will create complications in a proportion of people over 5 years.
TREATMENT PARAMETERS

4 factors are important when considering the effects of radiation:
1. Total dose
2. Dose fraction size
3. Total volume treated
4. Elapsed time
1) For a given dose of radiation, normal tissue tolerance increases when larger volumes are irradiated.
2) Prolonging the treatment time may risk sparing the tumour without actually reducingthe risk of side effects.
3) The effect on tissue varies from mild structural alteration to severe anatomic and functional derangement with
necrosis.
4) Injury may be d/t radiation effect on the microvasculature or the support tissues.
RADIATION EFFECTS
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
Acute vs Late

There is no association between intensity of acute reaction to severity of late effects.
Radiation effects on skin
 Cutaneous radiation damage effects frequently present to the plastic surgeon.
 TD 5/5 of skin is 55Gy. 70Gy leads to TD 50/5.
ACUTE EFFECTS (Within the 1st 6 mths of Rx)
1. Erythema – the earliest S/E. Peaks at day 8. Area conforms to shape of irradiated field.
2. Dry desquamation - occurs at moderate dose level.
3. Moist desquamation – high doses - serous oozing from the surface occurs (Rx of skin Ca)
CHRONIC EFFECTS (After 6 mths of Rx)
1) Pigmentation changes – hyperpigmentation. Increased transfer of melanin to keratinocytes
2) Thickening and fibrosis of skin and subcutaneous tissue
3) Telangiectasias
4) Dysfunction of sebaceous and sweat glands
5) Alopecia
6) Xerostomia
7) Necrosis
8) Tumorigenesis
9) Osteoradionecrosis
Pathophysiology by Cell Type
1. Keratinocytes

The epidermis is composed mostly of keratinocytes, melanocytes and other dendritic cells.

Layers:
1) Stratum corneum
2) Stratum lucidum
3) Stratum granulosum
4) Stratum spinosum
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5) Stratum germanitivum
(rest on the BM above the dermis. Cell division +++)

Cells constantly shed from the cornified layer.

Epidermal renewal takes 60-70 days.

Cells in the G2-M phase (those that are rapidly dividing) are the most sensitive to radiation. In skin these
are the cells in the basal layer.
Early Changes (dose dependent):
 A single small dose of radiation (even solar) may result in the activation of proteolytic enzymes – leads to
increase in capillary permeability and a local inflammatory response. An erythematous response may start
within a few hrs and last for 2-3 days. It usually does not cause permanent pigmentory changes.
 Larger doses will kill some epidermal cells. With re-population dry desquamation occurs.
 Even larger doses will destroy the whole population resulting in dermal exposure and wet desquamation.
Doses of radiation used in radiotherapy usually result in reproductive death of the cell and not immediate cell
death. Cells therefore do not multiply and are lost slowly from the surface at the rate of normal turnover.
 Reepithelialisation occurs from the hair follicles and wound edges.
 If acute radiation damage is severe enough, the epidermis separates from the dermis and a bulla is formed.
Late radiation changes:
 Fibroblast populations undergo not only total cellular depletion in response to radiation exposure but show a
reduced activity or aberrant ability to intracellularly produce and extrude collagen into the surrounding tissue.
 Irregular epidermis with areas of atrophy alternating with areas of hyperplasia,
 Hyperkeratosis (thickening of the stratum corneum) is also seen.
 Degeneration (oedema and homogenization) may occur.
 The nuclei may become atypical.
 The cells arranged in a disorganised fashion.
 Telangiectatic vessels
 Irregular epidermal downgrowth.
 Epidermis is fragile, prone to injury and tumour development
2. Melanocytes
 Pigment producing cells of the epidermis derived from neural crest.
 Located in the basal layer.
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 One melanocyte per every 10 keratinocytes.
 Epidermal melanin unit = 1 melanocyte + about 36 viable keratinocytes.
 Melanin is transferred from the melanocytes to the keratinocytes via melanosomes.
 Radiation exposure may result in increased pigmentation.
 Radiation may cause release of pigment from the melanocytes into the dermal macrophages (melanophages) 
darkening of the skin.
 Higher doses of radiation may destroy the melanocytes resulting in reduced pigmentation.
 May get areas of alternating pigmentation.
3. Dermal fibroblasts and Collagen

inflammation, oedema, hyalinization of collagen bundles.

diminished ability of dermal fibroblasts to proliferate may result in reduced healing.

dermal necrosis may lead to ulcer formation.

fibrosis

radiation fibroblasts (large, unusual, stellate cells).
4. Cutaneous Vasculature
EARLY
 permeability of superficial vessels - erythema.
 Endothelial proliferation
 Oedema of vessel walls
 Thrombosis
LATE
 Telangiectasia of superficial vessels
 Thrombosis and recanalisation of deeper vessels
 Some vessels may appear healthy, others completely occluded.
 Lymphoedema of the superficial dermis
5. Cutaneous Adnexal Structures
Hair follicles undergo a cyclic growth.
1. Anagen phase - active growth. Actively growing hairs arise from anagen follicles.
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
Mitotically active phase - prone to radiation.

Anagen phase lasts + 3 yrs.

86% of hair follicles on the scalp are in the anagen phase at any one time.
2. Catagen phase is the transition period between active growth and resting phases.

The shortest phase (2-3 weeks) and the least common (1%).
3. Telogen phase is the resting phase (13% at any one time).

1-9 months (average 3 months) – increases with age

Hair lies dormant on follicle until new anagen hair pushes it out.
Effects of Radiation:

Hair dysplasia

Alopecia

Impaired metabolism of growing hair follicles

With higher doses, permanent hair loss is more likely. Hair follicles become replaced by scar: chronic
radiation dermatitis. With loss of hair follicles, epidermal healing may not occur (since this occurs from
the follicles).

Pigment changes can occur.

Sebacceous glands may be destroyed by radiation.

Eccrine glands are the most resistant of the epidermal appendages.
TREATMENT OF EARLY AND LATE RADIATION CHANGES OF SKIN
EARLY
 Supportive: Avoid trauma and irritation.
 Use mild soaps, antipruritics, creams and lotions.
 A/B creams and lotions (SSD etc).
LATE
 Good radiation technique important in prevention of these problems.
 Sun screens, especially for hypopigmentation.
 FU regularly (look for secondary tumours).
 SSG or flap may be required.
 Physio to prevent contractures.
RADIATION EFFECT ON WOUND HEALING
Effect of Direct Skin Irradiation:
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EARLY

Healing is impaired because of the toxic effect of radiation on fibroblasts.

Collagen deposition and remodelling are affected by the impaired fibroblasts.
LATE

Cutaneous dermal atrophy

Fibrosis and contracture
Fibroblasts from irradiated skin grow at a much slower rate than those taken from normal skin of the same
patient.
Injection of radiation wounds with normal fibroblasts improves wound healing.
Radiation of less than ~8Gy will not affect wound healing.
Radiation above ~20Gy will not impair wound healing further.
It has been shown that wound healing is less adversely affected if radiation is given in several fractions rather
than as one big dose.
Pre-wounding radiation (whether 1 hr or 95 days prior to wounding) markedly impaired wound healing.
Post-wounding radiation at 7 and 12 days after wounding has little effect on wound strength.
50 Gy 4-6wks pre-op  no increase in surgical morbidity.
10 Gy 24 hrs pre-op  significant increase in surgical morbidity.
A modest dose of properly fractioned RT given 3-6 wks prior to surgery should not increase morbidity.
Doses > 50 Gy or radiation just prior to surgery should be avoided.
Fewer problems occur when radiation follows surgery.
Surgery done on skin with chronic radiation damage has a significantly increased incidence of Cx.
CARCINOGENESIS
Many treatments target cellular DNA and therefore risk inducing later tumours.
When is the risk increased?:
When Intermediate doses of radiation have been used there is a greater risk than when large doses have been
used; perhaps because large doses kill cells.
Children have a higher risk of subsequent Ca.
Where lower doses of radiation were originally used to treat a benign condition, there is an increased risk of Ca.
Where areas of chronic radiation damage are exposed to the sun, the risk is higher.
UV radiation may be needed to promote tumour formation in skin exposed to ionising irradiation.
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Small daily fractions reduces the risk.
Tumour Type

Usually give rise to BCC and SCC.

SCC arising in areas of radiation damage are highly malignant and tend to mets.

Sarcomas may also occur in previously irradiated skin.

Patients who develop skin tumours in irradiated skin tend to do poorly.
General Rules:

A modest dose of properly fractioned pre-op radiation given 3-6 weeks prior to surgery should not increase
morbidity

Doses > 50 Gy or irradiation just prior to surgery should be avoided

Fewer problems occur when radiation follows surgery

Surgery done on skin with chronic radiation damage has a significantly increased incidence of
complications