5Rs of Radiation Therapy
Caesar Barare
KMTC Manza Campus
Introduction
• Practicalities of radiation therapy:
• Define the target to treat
• Design the optimal technical set-up to provide uniform irradiation
of that target
• Choose that schedule of treatment that delivers radiation to that
target in such a way as to maximise the therapeutic ratio
• Radiobiology allows the optimization RT schedule for
individual patients in regards to:
• Total dose and number of fractions
• Overall time of the radiotherapy course
• Tumour control probability (TCP) and normal tissue complication
probability (NTCP)
Causative Effects
Direct Action
• Radiation may impact the
DNA directly, causing
ionization of the atoms in
the DNA molecule (“direct
hit”).
• Dominant process in the
interaction of high LET
particles such as neutrons
or alpha particles with
biological material.
Indirect Action
• Radiation interacts with
non-critical target atoms or
molecules, usually water,
resulting in the production
of free radicals, which are
atoms or molecules that
have an unpaired electron
and thus are highly reactive
• Free radicals attack critical
targets such as the DNA.
Summary 1
Direct Action:
• Photon ejects an electron
which produce a biological
damage
Indirect Action:
• Electrons produce free
radicals which break
chemical bonds and
produce chemical changes
“5 R’s” of Radiotherapy
• Repair of cellular damage; (few hours)
• Reoxygenation of the tumour; (hours to few days)
• Redistribution/ Reassortment within cell cycle;
(few hours)
• Repopulation of cells; (5 – 7 weeks)
• Radiosensitivity
• The biological factors that influence the response
of normal and neoplastic tissues to fractionated
radiotherapy
Repair
Repair
• Repair is very effective because DNA is
damaged significantly more due to ‘normal’
other influences (e.g. temperature, chemicals)
than due to radiation
• Types of Damage
• Lethal—irreversible, irreparable, leads to cell death
• Sublethal (SLD)—repaired in hours; if a second dose is
given, can interact with more damage to create lethal
damage; represents shoulder on cell survival curve.
• Potentially Lethal Damage (PLD)—can be modified by
the post-irradiation environment.
Repair
• Normal tissues need to repair all repairable
radiation damage prior to giving another
fraction of radiation;
• a minimum interval between fractions of 6 hours
• Spinal cord seems to have a particularly slow repair therefore, breaks between fractions should be at least
8 hours if spinal cord is irradiated
Repopulation
Repopulation
• Damage and cell death occur during the
course of the treatment may induce an
increased rate of cell proliferation.
• Most important in early-responding normal tissues (e.g., skin, GIT)
as well as tumours.
• Influences local tumour control.
• Local control is reduced by ~0.5% for each day that overall
treatment time is prolonged; this provides for rationale for
accelerating fractionated radiation therapy.
• Overall treatment time would be expected to be less important for
slower-growing tumors such as prostate or breast cancer.
Reoxygenation
Reoxygenation 1
• Oxygen is an important enhancement for
radiation effects (“Oxygen Enhancement
Ratio” (OER)
• The tumor may be hypoxic (in particular in the center which may
not be well supplied with blood)
• One must allow the tumor to re-oxygenate, which typically
happens a couple of days after the first irradiation
• Tumour response to large single doses of
radiation is dominated by the presence of hypoxic
cells within them, even if only a very small
fraction of the tumour stem cells are hypoxic.
Reoxygenation 2
• Reoxygenation can result in a substantial
increase in the sensitivity of tumours during
fractionated treatment.
• Sensitivity to radiation increases with oxygen.
• Tumours under 1 mm in size are fully oxic, but tumours over this
size develop regions of hypoxia.
Reoxygenation 3
• Reoxygenation Mechanisms may include;
• Reopening of temporarily occluded blood vessels (minutes)
• Reduced respiration of lethally damaged cells (minutes to hours).
• Resorption of dead cells leads to decreased distance from
capillaries to tumor cells, improving their oxygen supply (days).
• Oxygen Enhancement Ratio (OER)
• Ratio of radiation doses in hypoxic and aerated conditions to get
the same biological effect; dependent on LET
Cell Cycle
Cell Cycle 1
G0 = Cell rests (it’s not dividing) and does its normal work in the body
G1 = RNA and proteins are made for dividing
S = Synthesis (DNA is made for new cells)
G2 = Apparatus for mitosis is built
M = Mitosis (the cell divides into 2 cells)
Cell Cycle 2
• G0 phase (resting stage): The cell has not yet started to
divide. Cells spend much of their lives in this phase,
carrying out their day-to-day body functions, not dividing or
preparing to divide. Depending on the type of cell, this
stage can last for a few hours or many years. When the cell
gets the signal to divide, it moves into the G1 phase.
• G1 phase: The cell gets information that determines if and
when it will go into the next phase. It starts making more
proteins to get ready to divide. The RNA needed to copy
DNA is also made in this phase. This phase lasts about 18 30 hours.
Cell Cycle 3
• S phase: In the S phase, the chromosomes (which contain
the genetic code or DNA) are copied so that both of the
new cells to be made will have the same DNA. This phase
lasts about 18 - 20 hours.
• G2 phase: More information about if and when to
proceed with cell division is gathered during this phase.
The G2 phase happens just before the cell starts splitting
into 2 cells. It lasts from 2 -10 hours.
• M phase (mitosis): In this phase, which lasts only 30 - 60
minutes, the cell actually splits into 2 new cells that are
exactly the same.
Redistribution/
Reassortment
Redistribution 1
• Cells have different radiation sensitivities in
different parts of the cell cycle Highest
radiation sensitivity; early S and late G2/M
phase of the cell cycle
• Variation in the radiosensitivity of cells in
different phases of the cell cycle results in the
cells in the more resistant phases being more
likely to survive a dose of radiation.
Redistribution 2
• Two effects can make the cell population more
sensitive to a subsequent dose of radiation.
• Some of the cells will be blocked in the G2 phase of the cycle, which is
usually a sensitive phase.
• Some of the surviving cells will redistribute into more sensitive parts of
the cell cycle.
NB: Both effects will tend to make the whole
population more sensitive to fractionated
treatment as compared with a single dose.
Redistribution 3
• Distribution of cells in different phases of the
cycle is normally not something which can be
influenced - however, radiation itself
introduces a block of cells in G2 phase which
leads to a synchronization
• One must consider this when irradiating cells
with breaks of few hours.
Radiosensitivity
Radiosensitivity 1
• Relative susceptibility of cells, tissues, organs,
organisms, or other substances to the
injurious action of radiation [Seibert (1996)].
• Bergonie and Tribondeau (1906) realized that
cells were most sensitive to radiation when
they are:
• Rapidly dividing
• Undifferentiated
• Have a long mitotic future
Radiosensitivity 2
• For a given fractionation course (or for singledose irradiation), the haemopoietic system
shows a greater response than the kidney, even
allowing for the different timing of response.
• Similarly, some tumours are more
radioresponsive than others to a particular
fractionation schedule, and this is largely due to
differences in radiosensitivity.
Radiosensitivity 3
• Contributing factors to Radiosensitivity;
• High metabolism tumour cells was early recognized as a prominent
factor in radiosensitivity
• Tumour rate of growth.
• Increased or unstable vascularity also goes with rapid growth
• Above factors when combined render rapidly
growing tumours sensitive to radiation
Deacon J, Peckham M. J, Steel GG. Radiother Oncol. 1984 Dec;2(4):317-23.
Radiosensitivity 4
Decreasing Sensitivity Order:
A: Lymphoma, Myeloma,
Neuroblastoma.
B: Medulloblastoma, SCLC
C: Breast, Bladder, Cervix
D: Pancreas, Colo-Rectal,
Squamous Lung.
E: Melanoma,
Osteosarcoma,
Glioblastoma, RCC
Deacon J, Peckham MJ, Steel GG. Radiother Oncol.
1984 Dec;2(4):317-23.
Summary
•
•
•
•
•
•
•
Redistribution, Repair are benefits of fractionation
Repopulation is the negative associated with fractionation
Repair occurs ib both normal and tumour cells
Redistribution occurs in cycling cells mostly in tumour
Reoxygenation occurs only in tumour
Repopulation occurs in tumour cells
Repair and Repopulation tend to make the tissue more
resistant to second dose of radiation
• Redistribution and Reoxygenation tend to make tissue
more radiosensitive
• Overall sensitivity of tissue depends on the Fifth “R”:
RADIOSENSITIVITY
Last Word
• Radiosensitivity is a newer member of the R's.
• Apart from repair pathways, redistribution of
cells, reoxygenation of malignant cells and
repopulation there is an intrinsic Radiosensitivity
or Radioresistance in different cell types.
• Radiosensitivity expresses the response of the
tumour to irradiation.
• Malignant cells have greater reproductive
capacity hence are more radiosensitive
6th R
Boustani et al; 2019. The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response. MDPI, Basel, Switzerland
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