Hall Book Ch 20 (Clinical Response to Normal Tissues) Flashcards
Most effects of radiation on normal tissues are caused by cell killing, but some, such as nausea, vomiting, or fatigue experienced by patients following irradiation of large volumes including the abdomen, may be mediated by ( ).
radiation-induced inflammatory cytokines
Apparent radioresponsiveness of a tissue depends on ( ).
inherent sensitivity of cells, kinetics of the tissue or cell population, and the way cells are organized in that tissue
Sensitivity of actively dividing cells is expressed by their survival curve for reproductive integrity.
The radiation dose needed to destroy the functioning ability of a differentiated cell is far greater than that necessary to stop the mitotic activity of a dividing cell.
The shape of the dose–response relationship for functional end points, obtained
from multifraction experiments, is more pertinent to radiotherapy than
clonogenic assays.
The time interval between irradiation and its expression in tissue damage
depends on the life span of mature functional cells and the time it takes for a
cell born in the stem compartment to mature.
Hyperthermia damage is expressed early compared with radiation damage (see
Chapter 28).
Both early and late effects may develop in one organ system because of injury
to different target cell populations or tissue elements.
The α/β ratio (the dose at which the linear and quadratic components of
radiation damage are equal) may be inferred from multifraction experiments
in systems scoring nonclonogenic end points.
Tolerance doses for late effects are more sensitive to changes in dose per
fraction (low α/β value) compared with tolerance doses for early effects.
Spatial arrangement of FSUs is critical to the tolerance of some normal tissues.
In some tissues (e.g., spinal cord), the FSUs are arranged serially (like links in
a chain), and the integrity of each is critical to organ function.
Tissues with a serial organization (e.g., spinal cord) have little or no functional
reserve, and the risk of developing a complication is less dependent on
volume irradiated than for tissues with a parallel organization. The risk of
complication is strongly influenced by high-dose regions and hot spots.
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A tissue with intrinsically high tolerance may fail as a result of the inactivation
of a small segment (as in the spinal cord); a tissue with an intrinsically low
tolerance (kidney and lung) may lose a substantial number of its functional
units without impact on clinical tolerance.
Casarett’s classification of tissue radiosensitivity is based on histopathologic
observations.
In terms of radiosensitivity based on histologic observation of cell death,
parenchymal cells fall into four categories, from most sensitive to most
resistant:
1. Stem cells of classic self-renewal tissues, which divide regularly
2. Differentiating intermitotic cells, which divide regularly but in which
there is some differentiation between divisions and which are variably
differentiated
3. Reverting postmitotic cells, which do not divide regularly but can divide
under the appropriate stimulus
4. Fixed postmitotic cells, which are highly differentiated and appear to
have lost the ability to divide
Connective tissue and blood vessels are intermediate in radiosensitivity
between groups II and III.
Michalowski’s classification divides tissues into H- and F-type populations,
which respond differently to radiation.
Many tissues are a hybrid of H- and F-type.
The response of a tissue is influenced greatly by a host of growth factors,
including interleukin-1 and 6, basic fibroblast growth factor, platelet-derived
growth factor β, TGF-β, and TNF.
Early radiation response in the skin is caused by damage to the epidermis; the
late response reflects damage to the dermis.
The hematopoietic system is very sensitive to radiation, especially the stem
cells. The complex changes seen in peripheral blood count after irradiation
reflect differences in transit time from stem cell to functioning cell for the
various circulatory blood elements.
The effect of irradiation on the immune function is complex, depending on the
volume irradiated and the number of surviving cells. A total body dose of 3.5
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to 4.5 Gy inhibits the immune response against a new antigen.
The cellular organization of the lining of the gastrointestinal tract is similar to
that of the skin, but the life span of the differentiated cells is shorter. Both
early and late sequelae can occur.
Oral mucosa: Damage to the oral mucosa during radiotherapy for head and
neck cancer is very important for both the comfort and welfare of the patient.
Xerostomia can interfere with nutrition and dental health.
Esophagus: Early and late effects can occur and lead to difficulty in
swallowing. Tolerance is 57.5 Gy in 10 fractions (acute effects limit).
Stomach: Irradiation of the stomach often leads to nausea and vomiting.
Tolerance doses range from 40 to 50 Gy.
Small and large intestines: Both early and late complications can occur.
Tolerance dose is about 50 Gy for the small intestine, slightly higher for the
large intestine, and 70 Gy for the rectum.
The lung is an intermediate- to late-responding tissue. Two waves of damage
can be identified: an acute pneumonitis and a later fibrosis. The lung is
among the most sensitive late-responding organs. Pulmonary damage also
may occur following chemotherapy.
Together with the lung, the kidney is among the more radiosensitive lateresponding critical organs. FSUs are in parallel, with only about 1,000 stem
cells in each. A dose of about 30 Gy in 2-Gy fractions to both kidneys results
in nephropathy.
In terms of radiosensitivity, the liver ranks immediately below the kidney and
lung. FSUs are in parallel so that much larger doses are tolerated if only part
of the organ is exposed. Fatal hepatitis may result from 35 Gy (conventional
fractionation) to the whole organ.
Cell renewal is low in the bladder epithelium, so proliferation following
irradiation is delayed. Frequency of urination increases in parallel with loss
of surface cells. Absence of surface cells explains irritation by urine.
The nervous system is less sensitive to radiation than other late-responding
organs, such as the kidney or lung.
Brain: Histopathologic changes that occur in the first year are most likely to
involve white matter; at later times, gray matter usually shows changes
accompanied by vascular lesions. Radionecrosis may occur accompanied by
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cognitive defects.
Spinal cord: Early demyelinating injuries may develop after doses as low as
35 Gy but are usually reversible. For late damage, the TD5/5 is about 50 Gy
for a 10-cm length of cord. By 70 Gy in conventional fractions, the incidence
of myelopathy would be 50%. FSUs are in series, but once the field exceeds
a few centimeters, the treatment volume has little effect. Tolerance dose
shows little dependence on overall time but depends critically on dose per
fraction (α/β is low). If two doses per day are used, the interfractionation
interval must be more than 6 hours because there is a slow component of
repair.
In the testes, a dose of 0.1 to 0.15 Gy leads to temporary sterility. A dose of 6
to 8 Gy in 2-Gy fractions leads to permanent sterility. Such doses have little
effect on libido. The stem cells are more radiosensitive than the differentiated
cells, so continuous or fractionated radiation is more effective than a single
acute dose.
Sterilization by radiation to the ovaries is immediate (no latent period, as in the
male) and leads to all the changes associated with menopause.
Among the female genitalia, tolerance doses for the vagina are high: 90 Gy
before ulceration and 100 Gy for the development of a fistula. For
intracavitary treatment, doses to the cervix and uterus may reach 200 Gy.
Late damage to many different tissues and organs is mediated to some extent
by effects on the vasculature. Arterial damage may occur after fractionated
doses of 50 to 70 Gy, but capillaries are damaged by doses above about 40
Gy.
In its tolerance to radiation, the heart is intermediate between the kidney or
lung and the central nervous system. The most common radiation-induced
heart injury is acute pericarditis, which seldom occurs in the first year
posttherapy. A dose of 40 to 50 Gy in conventional fractions induces about
an 11% incidence. The α/β ratio is low (1 Gy) so that fractionation results in a
substantial sparing. Protection of part of the heart reduces symptoms.
Growing cartilage is particularly radiosensitive in children: 10 Gy can slow
growth, and deficits in growth are irreversible above about 20 Gy. In the
adult, osteoporosis of the lower mandible may be a serious complication
following radiotherapy for cancer of the buccal cavity. Fractures of the
humeral or femoral head may occur; the TD50/5 is about 65 Gy.
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Over the past several decades, with the development of more sophisticated
three-dimensional treatment planning systems, numerous studies in the
literature have reported associations between dosimetric parameters and
normal tissue outcomes. QUANTEC summarized the available data in a
clinically useful format. It is intended to be an update of the data published
by Emami and colleagues in 1991, which is widely used despite the fact that
it has often been criticized.
The RTOG and EORTC introduced the SOMA classification for LENT:
SOMA is an acronym for subjective, objective, management criteria with
analytic laboratory and imaging procedures.
