Page 232 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 13 Radiation Oncology 211

physical measurelike the linear energy transfer (LET), which injury of normal tissue occurred when radiation was fraction-
1
measures the amount of energy transferred per unit path length. ated. Coutard’s recommendations were 2 Gy fractions delivered
Monday through Friday for 6 to 8 weeks with a total dose of 60
LET is a factor in RBE, but RBE also considers factors such as
VetBooks.ir biologic endpoint, fractionation, radiation dose rate, and dose. to 80 Gy. In veterinary medicine, standard fractionation denotes
The RBE of 1 Gy of electrons and photons is the same, but 1
a regimen delivering 2.7 to 4.0 Gy per fraction, three to five times
Gy of neutrons or heavy charged particles such as carbon causes per week, to a total dose of 42 to 57 Gy. Hyperfractionation refers
substantially more damage. 38,39 RBE essentially compares the bio- to schedules in which the dose per fraction is reduced and the total
logic difference between specific types of radiation relative to the dose is increased. In human radiation oncology, this approach has
effect of photons. Protons, which are commonly used in human been associated with improved outcome for a number of tumor
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radiation facilities, have a slightly higher RBE than photons and types, including oropharyngeal carcinoma. Accelerated RT
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electrons. Protons and heavy charged particles also share unique describes a treatment regimen in which the overall time of treat-
properties in dose distribution that can be beneficial in treatment ment is reduced. Hypofractionation describes the administra-
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planning. 41,42 tion of higher doses per fraction given in a smaller number of
fractions. Compared with most conventional human protocols,
Alternative Methods of Radiation Cell Death the protocols used in veterinary medicine would be considered
hypofractionated and accelerated. The response of tumor and
Radiation-induced apoptosis is the second most common form of normal tissues to conventionally fractionated RT (regardless of
cell death after irradiation, but it is highly cell-type dependent. human or veterinary oncologist prescribed) has been described by
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Lymphoid tissues are particularly prone to apoptosis, which may Withers as the “Four Rs” of RT: repair of DNA damage, redistri-
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be the dominant form of cell death in these tissues. Apoptosis can bution of cells in the cell cycle, reoxygenation of tumor cells, and
occur spontaneously in tumors, although the degree of occurrence repopulation of tumor and normal tissues. 3
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can vary even within the same tumor type. Radiation responsive Division of the total radiation dose into fractions is important
tumors may undergo greater levels of radiation-induced apoptosis for a number of reasons. The first reason is to exploit potential dif-
than more radioresistant tumors. Apoptosis of endothelial cells ferences in repair capabilities between tumors and normal tissues.
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may indirectly affect tumor cell kill by leading to vascular col- Slowly dividing cells are somewhat less sensitive to small doses of
lapse. Vascular collapse has been recognized to play a role in the radiation than more rapidly dividing cells; however, they appear to
overall response to radiation therapy. Apoptosis of endothelium become relatively more sensitive if radiation is delivered in larger
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primarily occurs when high-dose fractions are administered and doses per fraction. If smaller doses per fraction are used, normal
may play a more important role when hypofractionated radiation tissues with slowly dividing cells can be spared relative to tumor
is delivered. 47–49 tissues with rapidly dividing cells. 58
The bystander effect, defined as biologic effects observed in Other events that occur between radiation fractions are cell
cells not traversed by radiation but in proximity, may affect some cycle redistribution and reoxygenation. When a fraction of RT
50
cells, but this has not been well quantified in vivo. Autoph- is administered, many of the cells in the sensitive portions of
agy, cell senescence, oxidative stress, and immune response may the cell cycle are killed. During the interval between fractions,
also play roles. 50,51 Abscopal effects refer to distant sites, such as cells from the late S-phase, which are more likely to be alive than
when a tumor irradiated in one part of the body affects tumors other cells, progress to more sensitive parts of the cell cycle. This is
in other locations. Abscopal effects may be associated with an known as redistribution. 29,30 Tumor hypoxia is a common feature
50
50
enhanced immune response. occurring in many solid tumors due to decreased vascular density
and malformed tumor vessels. Chronic hypoxia, also known as
Tumor Stem Cells diffusion-limited hypoxia, is caused by limitation in oxygen dif-
fusion to cells further away from tumor vessels. 36,37,59 Perfusion-
As early as 1973, it was recognized that the number of injected limited related hypoxia is due to temporary closing or blockage
tumor cells from a variety of spontaneous cell lines to induce of malformed blood vessels. The tumor microenvironment is
tumor formation in 50% of recipients varied from 21 to 24,000 constantly changing and is itself affected by radiation. After a
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cells. 52,53 This tumor-forming ability in vivo appears to correlate fraction of radiation, oxygenated cells die, allowing hypoxic cells
in many cases with the percentage of cells within the tumor bulk closer access to vessels. The location of acutely hypoxic cells var-
possessing a stem-cell-like phenotype. Cancer stem cell markers, ies based on the opening and closing of vessels and is transient.
such as CD24 and CD44, have been identified, but the relation- Tumor hypoxia cannot be predicted by tumor size or histologic
ship between the markers and stem cell characteristics remains type but is thought to contribute to treatment failure. In experi-
under investigation. 54,55 It is hypothesized that the number or mental models, the pattern for reoxygenation and the extent of the
percentage of tumor stem cells and their intrinsic radiation sensi- reoxygenation varies. 60,61
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tivity predict radiocurability. Tumor stem cells are being inten- The length of time over which RT is administered is impor-
sively investigated as a potential target for therapy. tant primarily because of tumor repopulation but also because
of rapidly proliferating normal tissues, such as mucosa and skin.
Principles of Fractionated Radiation Therapy Tumor cells that have not been destroyed by irradiation con-
tinue to replicate during the course of therapy. This process is
Time, Dose, and Fraction Size exacerbated by a phenomenon known as accelerated repopula-
tion. 3,62,63 It is believed that after approximately 4 weeks of ther-
Early radiation oncologists found that higher total doses could apy, tumors repopulate more rapidly than initially. 3,63 The reason
be given if the doses were divided into smaller doses, known as for this is not clear, but the phenomenon could be related to (1)
fractions. Coutard, a radiation oncologist at the Curie Institute a reduction in the cell cycle time, (2) an increase in the num-
in Paris, observed that tumor response was improved and less ber of tumor cells that are actively dividing (growth fraction),