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THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part I: The Basics of Brachytherapy
Version 1 - 22/10/2015
Radiobiology of LDR, HDR, PDR and VLDR Brachytherapy
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inactivate the free radicals, and fixation reactions that eventu-
ally lead to stable chemical changes in the DNA. Even at this
point, some repair occurs. For example, the restoration of vari-
ous DNA lesions, like DNA-strand or DNA-protein crosslinks,
base damages, single- (SSB) or double-strand breaks (DSB) can
be induced. Multiply damaged sites, i.e. combinations of these
damages, appear to be the basic changes leading to critical bio-
logical effects, e.g. cell death.
• A third,
biological phase
, much longer (seconds to years and
decades), during which the cells react to the inflicted chemi-
cal damage and interact with neighbouring cells, but also with
the immune system. It begins with the DNA Damage Response
(DDR) which is a highly complex and coordinated system of
enzymatic reactions that respond to the existing DNA damage.
It is estimated that 1 Gy, resulting in around 10
5
ionisations,
causes more than 5000 DNA base damages, about 1000 single
strand breaks and 20-80 double strand breaks, but will lead only
to a 30 % clonogenic cell kill in an average mammalian cell line.
This clearly indicates that in order to cope with different types of
radiation damage, mammalian cells have a variety of very effec-
tive
DNA repair systems
such as Base Excision Repair (BER) for
base damages, Single Strand Break Repair (SSBR) for SSB, and –
for DSB - Homologous Recombination (HR), Non Homologous
End Joining (NHEJ), and Single Strand Annealing (SSA), which
work with varying efficacy and fidelity (Wouters
et al.
). These
repair processes successfully repair the vast majority of lesions in
DNA. Thus only a few lesions are not or inadequately repaired,
and may lead to clonogenic cell death. Multiple damaged sites,
including DSB, are the main changes contributingto cell death.
Clonogenic cell death is defined as loss of the potential of a cell
to undergo an unlimited number of divisions. Clonogenic cells
may hence be considered as either normal tissue or tumour stem
cells. Clonogenic cell death after radiation exposure can occur in
various ways and at various times. Three pathways are dominant.
Mitotic death may occur at the first or at (3-4) subsequent cell
divisions, when the amount of accumulated DNA damage does
not allow for completion of the mitosis.
Apoptosis
is prominent in only a few cell types, such as lympho-
cytes and seminal epithelium, as well as in endothelial cells irra-
diated at high doses (> 15 Gy).
Thirdly, radiation induced differentiation (e.g. of epithelial cells)
or senescence (e.g. transformation of fibroblasts into fibrocytes)
can occur, which renders the cells non-clonogenic, although
still metabolically active, but with different metabolic and also
cell-interactive pathways.
The “stem cell hypothesis” postulates that the radiosensitivity of
a tissue is based on the number and the intrinsic radiosensitivity
of the tissue specific stem cells. Whenever these cells divide (in
a normal state), they produce a new stem cell (“self-renewal”)
and one other cell, which may either have a limited proliferative
capacity (“transit cell”) or directly undergo differentiation.
With regard to the time course, early (rather than acute) radia-
tion effects – by definition occurring during the first 90 days after
the onset of radiotherapy – are distinguished from late (chronic)
radiation effects that occur after months to many years.
In early responding, turnover tissues (hierarchically structured),
such as the bone marrow or the gastrointestinal mucosae, the
above mentioned stem cells produce transit cells, which are re-
sponsible for overall cell production, which is then counteracted
by the physiological cell loss. In late responding tissues, the tissue
specific stem cells produce differentiating cells that may also be
recruited into proliferation if there is a demand (flexible tissues).
In all tissues, there is a combined and complex response of all
exposed cell populations at the cellular level. In early respond-
ing tissues, the clinical radiation response is largely based on the
changes in the proliferating compartment (stem cell loss, defi-
cit in transit cells, hypoplasia, ulceration). Therefore, the time
to onset of early effects depends mainly on the turnover time of
the proliferative compartment, and is largely independent of the
radiation dose. For example, oral mucositis occurs at 9 days after
the accumulation of a radiation dose of 20 Gy (Van der Schueren
et al
. 1990). Based on the number of surviving tissue stem cells,
early radiation effects usually heal after a (biologically effective)
dose-dependent time interval. The more aggressive the treat-
ment, the earlier the effect and the longer it takes to heal.
In contrast, for late radiation effects, the parenchymal (i.e. stem
cell based) response is of varying importance. Here, endotheli-
al/vascular changes, such as dose dependent loss of capillaries,
vascular occlusions and telangiectasia – all associated with an
impairment of perfusion – are one major component. Radia-
tion- induced differentiation of fibroblasts, associated with a
substantial increase in connective tissue production, is another
predominant factor in radiation-induced tissue fibrosis. It must
be emphasized that these late tissue reactions are hence based
on changes in cellular functions in a complex way, rather than
(exclusively) on cell death.
4.
DOSE - TIME PATTERNS IN BT
With BT, treatment can be delivered in completely different time
patterns: either continuously at lower (VLDR/LDR) or medium
dose rates (MDR) or fractionated with smaller or larger fraction
sizes and intervals (HDR/ PDR) (Fig 5.3)
•
Low Dose Rate
(LDR) BT applies dose rates in the range be-
tween 0.4 and 2 Gy/h. However, in routine clinical practice,
LDR BT is usually delivered at dose rates between 0.3 and 1
Gy/h. This is compatible with manual or automatic afterload-
ing techniques.
•
Medium Dose Rate
(MDR) BT administers doses in the range
between 2 Gy/h and 12 Gy/h. MDR can also be delivered by
manual or automatic afterloading,
•
High Dose Rate
(HDR) BT delivers the dose at dose rates of 12
Gy/h and more (>20 cGy per minute), and only remote after-
loading is feasible because of the high source activity.
Two other dose rate schedules are also used in BT at present.
•
Pulsed Dose Rate
(PDR) BT delivers the dose in a large num-
ber of small fractions, called pulses, at short intervals, allowing
only for incomplete recovery in between. This aims to achieve
a radiobiological effect similar to low dose rate over the same
treatment time, typically a few days.