Early and late side-effects in radiation therapy

1 Hello and welcome to this lecture on the side-effects of

radiation therapy.

We will consider both early and late side-effects, but first we

will take a look at the biological effects of radiation at high
doses and the reasons why it can cause cell death.

2 What effect does radiation have on the cell?

When a patient receives radiation treatment, the radiation

deposits energy in the body. The energy is deposited in, or
transferred to, the tissues and their cells, and can cause
various types of damage. In principle, radiation can affect all
the parts of a cell, but it is the damage it does to DNA that has
the greatest consequences. It is this damage that is mostly
responsible for the death of cells. As a rule, cells repair DNA
damage very quickly, but if the damage is too great, the cell
dies.

Many factors influence the biological effects of radiation. The

presence of oxygen increases the risk that cell damage will
become permanent. In an oxygen-poor or oxygen-free
environment, cells can withstand radiation very well.
Biological effects are also influenced by the speed of the cell
cycle, how often the cells divide, and, of course, by the cell's
capacity to repair damage.
3 If its DNA is damaged by radiation, a cell initiates a cascade of
different reactions. The cell cycle is halted, preventing the cell
from dividing with damaged DNA. Either the cell succeeds in
repairing the damage completely, or if the damage cannot be
repaired, the cell commits ‘suicide’, or apoptosis.

4 The DNA molecule is made up of a double helix, as is

illustrated schematically in this diagram.

Radiation can damage both strands of the double helix at the

same time, or only a single strand. This image shows damage
to both strands—a double strand break. The damaged sites
are marked with green stars. Double strand breaks are the
hardest sort of damage for the cell to repair. They may be
repaired hastily, or more carefully, and there is a risk that the
DNA sequence will be altered—that the strands are made
whole again, but different to how they were before the
damage occurred. Sometimes a faulty repair becomes
apparent when it is time for the cell to divide, and the cell dies
 during cell division.
5 This picture also shows two damaged sites on a DNA
molecule, but here they are some distance from each other,
and affect only one strand at a time. These single strand
breaks are much simpler to repair, because in this case the
other strand is available as a template. Thus repairs like this
are nearly always perfect, leaving no errors in the DNA
sequence. Single strand breaks, and repairs to them, are very
common processes in our bodies.

6 There are large differences between different tissues’

sensitivity to radiation. Blood forming organs, are highly
sensitive, as are the testes. Connective tissue, on the other
hand, can tolerate high levels of radiation, as can muscles.
Tumours have the same sensitivity to radiation as their
corresponding healthy tissues. For example, tumours arising
in testicular tissue are very sensitive to radiation, while
tumours which originate in connective tissue or muscle are
largely insensitive to radiation.

There are some types of cell that rarely enter apoptosis. As I

mentioned earlier, the presence of oxygen plays a large role,
and there is a lack of oxygen at the centre of a tumour. This is
one reason why radiation treatment is fractionated. If the
treatment is repeated, the oxygen level at the centre rises as
the cells in the outer layers of the tumour are killed. In this
way, we can attack the cells which at the outset were poorly
oxygenated.

Different cells also have varying abilities to repair themselves,

and tumour cells in particular are much worse at repairing
damaged DNA than are healthy cells, a fact which we use in
radiation therapy.

Repopulation is a process by which cells that are not killed by

the radiation increase their rate of division—their growth
velocity—in order to compensate for the reduction. This is an
important factor in some organs. Reactions of mucous
membranes during radiation therapy can sometimes be
reduced if the treatment is fractionated, which gives the
healthy cells time to ‘catch up’ and compensate for the
damage.
7 The side-effects or reactions to radiation therapy are usually
divided into early and late side-effects.

The early effects are also sometimes called acute side-effects

or acute reactions. They are regarded as reversible; that is,
they heal once the radiation therapy has ended. Acute side-
effects above all affect various types of epithelial cells (for
example, mucous membranes and skin) and the blood
forming organs. Acute effects arise during the radiation
therapy or soon afterwards. Side-effects can peak a week or
so after the end of treatment, but then heal rather quickly.
 Late side-effects, on the other hand, are chronic, and afflict
soft tissues and internal organs. They arise months or years
after treatment, increase in severity with time, and cannot be
cured. It is important to avoid late side-effects, because they
lead to such chronic, permanent damage.
8 To understand what causes early side-effects, it is first
necessary to understand how the affected tissues function. A
characteristic of epithelia and blood-producing organs, such
as bone marrow, is that the replacement rate of cells is high.
Cells in these tissues are continually dividing. Epithelia serve
as a useful example here.

In the lower layer of our skin and our mucous membranes are
so-called stem cells, which are continually dividing. Newly
made skin or mucosal cells move slowly towards the surface,
and as they do so they differentiate, or mature. Mature cells
in the skin and mucous membranes have short lifetimes—
they die and are shed from the surface after only a few days—
but they are continually replaced from below by newly made
cells.

Mature epithelial cells tolerate radiation very well, but stem

cells are considerably more sensitive. Thus damage from
radiation is not noticed until a few weeks after exposure,
when worn out epithelial cells should be replaced from below:
if the stem cells have died, no new cells can be made.

Of course, the doses used in therapeutic radiation treatment

do not kill all the stem cells. The surviving stem cells can
therefore compensate for the losses very quickly once the
radiation treatment has ended.
9 Here you can see a schematic diagram of the structure of the
skin or a mucous membrane. The pink ovals at the top
represent the differentiated cells, which are resistant to
radiation damage. These can be thought of as the cells that
make up the functioning organ, for example the skin. The blue
ovals at the bottom are the stem cells, which are sensitive to
radiation. They are the ones that renew the skin by feeding
new cells up from below.

10 Here we see the situation after a high dose of radiation. Some

stem cells have been killed, and are marked red in the
diagram, but since the radiation-resistant cells were not
influenced by the radiation, the organ functions as normal,
despite the presence of dead stem cells in deeper layers
within it.

11 After a period in which radiation therapy has been given every

 day—the situation shown here is after a week or so—the
damage begins to be apparent. The differentiated cells are no
longer replaced by new ones. This is why the damage only
shows itself after a certain period of time. The length of that
period depends upon how quickly the surface cells are
normally replaced, and that varies from organ to organ.

12 In this diagram, the treatment has ended. Surviving stem cells

replace the dead ones and compensate for the losses. The
new cells differentiate as they are transported upwards, and
the damage heals with time.

13 Let us now look at what happens in tissues with late reactions

to radiation.

Cells in late-reacting tissues have a low replacement rate, or,

equivalently, a high proportion of cells at the resting stage of
the cell cycle. We have a situation in which individual cells can
die without affecting the function of the organ as a whole.
However, with time, an increasing number of cells become
dysfunctional because of the radiation. The most common
late side-effect is that the original tissue is replaced with
connective tissue, and the organ’s function is impaired. This
can become apparent long after the radiation treatment has
ended. The mechanisms are highly complex, and I will not
treat them at any more length in this lecture.
14 Here we can see a schematic diagram of a late-reacting tissue.
This represents an organ with no active cell division. The
organ carries out its task without needing replenishment with
new cells.
15 What happens in radiation treatment is that a proportion of
the cells are killed by the radiation. Because the proportion of
cells that die is not especially high, the organ continues to
function.

16 Some cells are damaged by the radiation, but live on and

continue to carry out their tasks.

17 The dead cells are replaced by connective tissue, resulting in

an organ that does not work as effectively.

18 In this case, even more cells have died and been replaced with
connective tissue.

19 To summarize:

Early side-effects are reversible and will heal after a time,

while late side-effects are chronic and should be avoided.

Early side-effects occur in epithelia—mucous membranes and

the skin. Late side-effects above all occur in soft tissues and
internal organs.

Early side-effects occur during the radiation therapy or soon

afterwards. Late side-effects arise months or years after the
therapy has ended.
Thank you for your attention.