Goal - therapeutic ratio Radiation therapy principles

Natalka Suchowerska Royal Prince Alfred Hospital Sydney, Australia

To cause maximum damage to tumour cells, while causing minimum damage to healthy tissue

To succeed
Cure/quality of life
Correct identification of target Precise delineation of target Precise delineation of healthy and of sensitive structures Accurate delivery of intended dose to delineated target, without breaching dose constraints to healthy tissue [dose measurement, dose calculation/prediction] Fractionation regime to maximise radiobiological advantage

Physics of radiobiology

Objective
On completion students will: understand why ionising radiation can be used to treat malignant cells know the type of radiation that does this best identify factors of significance to the success of this process

Assumed knowledge
Interaction of radiation with matter [electrons, photons and neutrons] Understand basic cell biology particularly DNA structure read Hall (1994)pp.2-8

Outline

Outline
/ ratio Cell Survival curve LET Cell Age Oxygen effect Organ structure Probability of effect Summary

Introduction Target theory Direct & Indirect Effect DNA strand breaks Repair mechanisms Linear Quadratic theory

Introduction
On discovery of ionising radiation, harmful effects not immediately realised partly because of latent effects. Early injuries were attributed to electrical effects, platinum particles from x-ray tube. Earliest known cases of cancer induced by radiation documented by Paracelsus (1493-1541), of uranium mine workers in Saxony:bergkrankheit (mountain sickness). Most extensive study of radiation effects has been 109 000 Hiroshima & Nagasaki survivors.

Introduction
Jan 29, 1896, 1 month after Roentgen announced discovery of x-rays, Emil Grubbe was treating breast cancer with 18 x 1 hour tmts. tmts. 1899 first curative tmts from Sweden reported [50 and 99 fractions] Fractionation due to primitive x-ray generators

General comments:

The interaction of radiation with a cell is a matter of chance [probability]. If an interaction occurs, the damage may not be expressed, in fact damage is more frequently repaired The initial deposition of energy occurs v. quickly The radiation is deposited in the cell randomly Radiation damage in cells, tissue and organ is indistinguishable from that produced by other trauma eg. chemicals Expression of damage occurs after a latent period, ranging from hours to years or even generations The DNA is the sensitive target in the cell

Target Theory
Certain sensitive targets within the cell must be hit to inactivate the cell Shape of cell survival curve is a function of the number of times a cell must be hit, before it loses its ability to reproduce

Direct and Indirect action of ionising radiation

Biological effect of radiation principally from DNA damage Critical Target Theory Direct action - occurs when the radiation is absorbed by a molecule known to be critical to maintain life of the cell e.g. DNA. This may initiate a series of events that lead to changes that may be lethal to cell [high LET radiation] high Indirect action - occurs when radiation interacts with other molecules in the cell, most importantly water. The products of these interactions may then go on to interact with the DNA [low LET radiation] low

Schematic diagram

Direct Action
When any form of radiation is absorbed by a living thing, there is the potential that that radiation will interact with some DNA (a critical target). This interaction may be of any of the forms you already know The interaction may be ionising, exciting or a chain of various interactions, all of which can lead to biological change in the DNA. This is the direct action or direct effect of radiation.

Indirect action
When any form of radiation is absorbed by a living thing, there is the potential that that radiation will interact with any atom or molecule in the cell, especially a water molecule, which constitutes 80% of the cell. Free radicals can then be produced, which are able to reach and damage a critical target of DNA. This method of biological interaction is called the indirect action or indirect effect.

Free radicals
A free radical is a molecule or atom, which is not combined to anything (ie. free) and carries an unpaired electron in its outer shell,i.e. its looking for something to interact with, or in purely scientific terms, it is in a state associated with a high degree of chemical reactivity. Imagine that some radiation has entered a body and interacts with a water molecule, of which there are plenty. If the water molecule is ionised H2O = H2O+ + eH2O is the water molecule H2O+ is an ion radical. Ion meaning it is electrically charged, because it has lost an electron and a radical because it has an unpaired electron in the outer shell, making it very reactive.

Ion radicals have a short life, usually no more than 10-10 seconds, before they decay to form free radicals. Free radicals are not charged, but do have an unpaired electron in the outer shell. The water ion radical can for example do the following: H2O+ + H2O = H 3O++ OH* H2O+, H3O+ are the ion radicals H2O is a water molecule OH* is a highly reactive hydroxyl radical, with 9 electrons, therefore one is unpaired. Hydroxyl radicals (OH*), are highly reactive and can go on to react with DNA. It is estimated that 2/3 of the x-ray damage to mammalian DNA is by hydroxyl radicals (Hall, 1994).

In summary the Indirect action is as follows: Incident x-ray photon Fast electron (e-) - occurs in 10-15 seconds Ion radical - live about 10-10 seconds Free radical - live about 10 -5 seconds Chemical changes from the breakage of bonds Biological effect - may be expressed in hours, days, months, years or not at all, depending on the consequences of the bonds broken.

Repair mechanisms
Single strand breaks Double strand breaks

Linear quadratic theory

Cell is inactivated by DSB Single hit, single lesion [random process], governed by Poisson statistics

Linear quadratic theory

2 separate ionising events, probability of one interaction causing one lesion is linearly proportional to dose, as is mean probability of second particle doing the same Mean probability of both events is D2 - mean probability per unit dose squared that such complementary events will occur

S = exp (-D)
S - surviving fraction of cells - average probability per unit dose that this will occur D - dose delivered

Linear quadratic theory

In general cell survival is described by: S = exp (-D -D2) (- - damage (irrepairable) (irrepairable) damage (repairable) NB of special interest is when D = -D2 - i.e. the curviness of cell survival curve

= 0.22 Gy-1, /=2.5Gy Gy-1, p301

LQ cell survival curve,

/ ratio
High / [straighter curve], characteristic of cell with little repair capability e.g. tumour cells [from 5 - 20 Gy] Gy] Low / [more curved], characteristic of high repair potential e.g.late responding normal tissue [1-4 Gy] Gy] This difference in cell survival curves provides rationale for fractionated radiation therapy treatment and explains radiobiological advantage

Effective survival Curve Effective

LET - Cell survival curve

Relationship between radiation dose and number of cells surviving [= clonogenic] clonogenic]

Cell Age

Oxygen Effect
OER for various types of radiation. OER - ratio of hypoxic to aerated doses needed to achieve the same biological effect OER particles - 1 x-rays - 2.5 neutrons - 1.6

Summary
Factors affecting Cell survival Dose Rate LET Cell Age Oxygen effect

Organ structure
Parallel e.g. kidneys, lungs Series e.g. spinal cord

Probability of Effect
Tumour control or severe complications

Stochastic effects eg. carcinogenesis

Based on the probability that a radiation dose will cause damage and the probability that that damage will be expressed.

Deterministic effects eg cateractogenesis, erythema

Have a threshold above which, the effect is more or less certain to appear. The severity increases with dose threshold

Severity of effect

Dose Thresholds for deterministic effects are well above those used in diagnostic radiology, but may be exceeded in RT or accidents

Summary
X-rays are indirectly ionising, producing fast recoil electrons Neutrons are also indirectly ionising, producing fast recoil protons, alpha particles and heavier nuclear fragments Biological effects of x-rays can be due to the direct effect or the indirect effect. Two thirds of x-ray biological damage is due to the indirect effect, which can be modified by chemical sensitisers or protectors Most high LET biological damage is due to the direct effect, which cannot be modified by chemical sensitisers or protectors The absorption of radiation is fast. The chemistry takes longer. The biological effect takes far longer if at all.

Summary
LQ model adequately describes cell survival for a single dose S = exp (-D -D2) (- - Sensitivity is affected by dose rate, LET, cell age and oxygen tension. Organ structure affects functional sensitivity Fractionation regimes are carefully designed to achieve the goals of RT