Radiation Protection in Radiotherapy

Radiation Protection in Radiotherapy
Part No 3, Lesson No 2 Biology IAEA Training Material on Radiation Protection in Radiotherapy Radiation Protection in Radiotherapy Part 3 Biological Effects Lecture 2: High Doses in Radiation Therapy Part 3: Biological effects Lesson 2: High doses delivered in radiotherapy Learning objectives: Upon completion of this lesson, the students will be able to: To understand the radiobiological background of radiotherapy To be familiar with the concepts of tumor control probability and normal tissue complication probability To be aware of basic radiobiological models which can be used to describe the effects of radiation dose and fractionation Activity: lecture Duration: 2 Materials and equipment needed: References: Radiobiology textbooks IAEA Training Material: Radiation Protection in Radiotherapy

Part 3, lecture 2: High doses in radiation therapy
Part No 3, Lesson No 2 Biology Overview Radiobiology is of great importance for radiotherapy. It allows the optimization of a radiotherapy 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) Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Objectives To understand the radiobiological background of radiotherapy To be familiar with the concepts of tumour control probability and normal tissue complication probability To be aware of basic radiobiological models which can be used to describe the effects of radiation dose and fractionation Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Contents 1. Basic Radiobiology 2. The linear quadratic model 3. The four ‘R’ s of radiotherapy 4. Time and fractionation Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology 1. Basic Radiobiology The aim of radiotherapy is to kill tumor cells and spare normal tissues In external beam and brachytherapy one inevitably delivers some dose to normal tissue Brachytherapy sources Beam 2 Beam 1 Beam 3 patient This is just a graphical illustration for the participants to appreciate the dilemma that one cannot give doe to one part of the body without giving some also to other parts. Therefore one must consider always both: normal tissue and target tumor Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Basic Radiobiology: target
Part No 3, Lesson No 2 Biology Basic Radiobiology: target The aim of radiotherapy is to kill tumour cells - they may be in a bulk tumor, in draining lymph nodes and/or in small microscopic spread. Tumour radiobiology is complex - the response depends not only on dose but also on individual radiosensitivity, timing, fraction size, other agents given concurrently (e.g. chemotherapy), … Several pathways to tumour sterilization exist (e.g. mitotic cell death, apoptosis (= programmed cell death), …) This slide summarizes many important factors of radiobiology - none is dealt with in great detail as it would be beyond the scope of the present course. However, it appears to be important to at least mention concepts such as apoptosis and chemotherapy. The complexity of tumor biology is a useful reminder to emphasize the need for a trained oncologist to head a radiotherapy program. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Survival curves This is an example for a survival curve in a large study on prostate cancer - in the context of the course it is not important to understand the study completely - the important messages are: the curve shows the number of actual surviving patients with time - the higher the curve, the better the outcome radiotherapy can make a difference in survival different practice improves survival Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Radiobiology: tumor Irradiation kills cells Different mechanisms of cell kill Different radio-sensitivity of different tumours Reduction in size makes tumour better oxygenated grow faster The reduction of the tumor in size means blood supply is typically better, therefore it is more radiosensitive due to reoxygenation and may also repopulate faster, off-setting some of the effects of cell kill. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Radiobiology: micrometastasis
Part No 3, Lesson No 2 Biology Radiobiology: micrometastasis Tumours may spread first through adjacent tissues and lymph nodes nearby Need to irradiate small deposits of clonogenic cells early Less dose required as each fraction of radiation reduces the number of cells by a certain factor This slide illustrates the need for proper target design - target in radiotherapy is not only the bulk tumour Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

The target in radiotherapy
Part No 3, Lesson No 2 Biology The target in radiotherapy The bulk tumour may be able to distinguish different parts of the tumour in terms of radiosensitivity and clonogenic activity Confirmed tumour spread Potential tumour spread The differentiation of different parts of the tumor can be done with modern imaging technology - in particular PET scanning has shown some promise. The lecturer can point out that a) different target areas may require different dose b) some target areas are just suspected tumor Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Reminder Palpable tumour (1cm3) = 109cells !!! Large mass (1kg) = 1012 cells - need three orders of magnitude more cell kill Microscopic tumour, micrometastasis = around 106 cell need less dose It is always important to get a feel for the order of magnitude. A bulky head and neck or lung tumor can have more than 10E12 cells Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Radiobiology: normal tissues
Part No 3, Lesson No 2 Biology Radiobiology: normal tissues Sparing of normal tissues is essential for good therapeutic outcome The radiobiology of normal tissues may be even more complex as the one of tumours: different organs respond differently there is a response of a cell organization not just of a single cell repair of damage is in general more important Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Different tissue types
Part No 3, Lesson No 2 Biology Different tissue types Serial organs (e.g. spine) Parallel organs (e.g. lung) Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Different tissue types
Part No 3, Lesson No 2 Biology Different tissue types Serial organs (e.g. spine) Parallel organs (e.g. lung) Effect of radiation on the organ is different Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Volume effects The more normal tissue is irradiated in parallel organs the greater the pain for the patient the more chance that a whole organ fails Rule of thumb - the greater the volume the smaller the dose should be In serial organs even a small volume irradiated beyond a threshold can lead to whole organ failure (e.g. spinal cord) Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Classification of radiation effects in normal tissues
Part No 3, Lesson No 2 Biology Classification of radiation effects in normal tissues Early or acute reactions Skin reddening, erythema Nausea Vomiting Tiredness Occurs typically during course of RT or within 3 months Late reactions Telangectesia Spinal cord injury, paralysis Fibrosis Fistulas Occurs later than 6 months after irradiation The lecturer can point out that this important distinction will be discussed more in the context of the linear quadratic model. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Classification of radiation effects in normal tissues
Part No 3, Lesson No 2 Biology Classification of radiation effects in normal tissues Early or acute reactions Late reactions Late effects can be a result of severe early reactions: consequential radiation injury This is potentially a very important effect currently discussed for epithelial tissues. It does not apply to spinal cord. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Late effects Often termed complications (compare ICRP report 86) Can occur many years after treatment Can be graded - lower grades more frequent The example shows the incidence of urinary and rectosigmoidal complications after prostate radiotherapy in a large group of patients Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

A comment on vascularisation
Part No 3, Lesson No 2 Biology A comment on vascularisation Blood vessels play a very important role in determining radiation effects both for tumours and for normal tissues. Vascularisation determines oxygenation and therefore radiosensitivity Late effects may be related to vascular damage Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Summary of radiation effects
Part No 3, Lesson No 2 Biology Summary of radiation effects Target in radiotherapy is bulk tumour and confirmed and/or suspected spread Need to know both effects on tumour and normal tissues Normal tissues need to be considered as a whole organ Radiation effects are complex - detailed discussion of radiation effects is beyond the scope of the course Models are used to reduce complexity and allow prediction of effects... The last sentence leads to the next section... Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology There is considerable clinical experience with radiotherapy, however, new techniques are developed and radiotherapy is not always delivered in the same fashion Radiobiological models can help to predict clinical outcomes when treatment parameters are altered (even if they may be too crude to describe reality exactly) IAEA Training Material: Radiation Protection in Radiotherapy

Radiobiological models
Part No 3, Lesson No 2 Biology Radiobiological models Many models exist Based on clinical experience, cell experiments or just the beauty or simplicity of the mathematics One of the simplest and most used is the so called “linear quadratic” or “alpha/beta” model developed and modified by Thames, Withers, Dale, Fowler and many others. The lecturer may want to delete the comment about models being just mathematically beautiful - in the opinion of the authors mathematical simplicity is not necessarily bad - it allows to attempt a meaningful fit to clinical data which is often very restricted. If a more complex model is fitted to clinical data, there may be too many parameters which would overparametrise the problem and derive a meaningless answer. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

2. The Linear Quadratic Model
Part No 3, Lesson No 2 Biology 2. The Linear Quadratic Model Cell survival: single fraction: S = exp(-(αD + βD2)) (n fractions of size d: S = exp(- n (αd + βd2)) Biological effect: E = - ln S = αD + βD2 E = n (αd + βd2) = nd (α + βd) = D (α + βd) S = survival D = total dose d = dose per fraction n = number of fractions alpha and beta are tissue specific constants RE = relative effectiveness BED = Biological effective dose E/α = BED = (1 + d / (α/β)) * D = RE * D Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Biological effectiveness
Part No 3, Lesson No 2 Biology Biological effectiveness E/α = BED = (1 + d / (α/β)) * D = RE * D BED = biologically effective dose, the dose which would be required for a certain effect at infinitesimally small dose rate (no beta kill) RE = relative effectiveness The lecturer should print the previous slide with comments (the explanation of the symbols and use as handout) Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 What is the physical unit for the a/b ratio?
Biology Quick question??? The exponent in the equation on slide 23 must be without dimensions. Therefore, alpha is measured in 1/Gy and beta in 1/(Gy)2 The a/b ratio is therefore given in Gy What is the physical unit for the a/b ratio? IAEA Training Material: Radiation Protection in Radiotherapy

BED useful to compare the effect of different fractionation schedules
Part No 3, Lesson No 2 Biology BED useful to compare the effect of different fractionation schedules Need to know a/b ratio of the tissues concerned. a/b typically lower for normal tissues than for tumour Here a/b stands for alpha over beta to avoid problems with the font used. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

The linear quadratic model
Part No 3, Lesson No 2 Biology The linear quadratic model The lecturer should spend a couple of minutes with the participants to discuss the graph - it is essential for the participants to note the logarithmic scale for survival the difference in curvature that the initial slope is determined by alpha that the curve has the same amount of alpha and beta kill when D = a/b Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

The linear quadratic model
Part No 3, Lesson No 2 Biology The linear quadratic model Alpha determines initial slope Beta determines curvature Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Rule of thumb for a/b ratios
Large a/b ratios a/b = 10 to 20 Early or acute reacting tissues Most tumours Small a/b ratio a/b = 2 Late reacting tissues, e.g. spinal cord potentially prostate cancer Part 3, lecture 2: High doses in radiation therapy

The effect of fractionation
Part 3, lecture 2: High doses in radiation therapy

Part No 3, Lesson No 2 Biology Fractionation Tends to spare late reacting normal tissues - the smaller the size of the fraction the more sparing for tissues with low a/b Prolongs treatment In general one can say, that fractionation has more effect on late effects as these have typically a low a/b ratio. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology A note of caution This is only a model Need to know the radiobiological data for patients Important assumptions: There is full repair between two fractions There is no proliferation of tumour cells - the overall treatment time does not play a role. The two assumptions will be discussed in the following... Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology 3. The 4 Rs of radiotherapy R Withers (1975) Reoxygenation Redistribution Repair Repopulation (or Regeneration) Withers R. The four Rs of radiotherapy. Adv. Radiat. Biol. 5: ; 1975 Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Reoxygenation Oxygen is an important enhancement for radiation effects (“Oxygen Enhancement Ratio”) The tumour may be hypoxic (in particular in the center which may not be well supplied with blood) One must allow the tumour to re-oxygenate, which typically happens a couple of days after the first irradiation This and the following slides are designed to be easily progressed through by the lecturer by just following the text flow. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Redistribution Cells have different radiation sensitivities in different parts of the cell cycle Highest radiation sensitivity is in early S and late G2/M phase of the cell cycle M (mitosis) G2 G1 S (synthesis) G1 Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Redistribution The 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. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Repair All cells repair radiation damage This is part of normal damage repair in the DNA Repair is very effective because DNA is damaged significantly more due to ‘normal’ other influences (e.g. temperature, chemicals) than due to radiation (factor 1000!) The half time for repair, tr, is of the order of minutes to hours Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Repair It is essential to allow normal tissues to repair all repairable radiation damage prior to giving another fraction of radiation. This leads to 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. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Repopulation Cell population also grows during radiotherapy For tumour cells this repopulation partially counteracts the cell killing effect of radiotherapy The potential doubling time of tumours, Tp (e.g. in head and neck tumours or cervix cancer) can be as short as 2 days - therefore one loses up to 1 Gy worth of cell killing when prolonging the course of radiotherapy Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Repopulation The repopulation time of tumour cells appears to vary during radiotherapy - at the commencement it may be slow (e.g. due to hypoxia), however a certain time after the first fraction of radiotherapy (often termed the “kick-off time”, Tk) repopulation accelerates. Repopulation must be taken into account when protracting radiation e.g. due to scheduled (or unscheduled) breaks such as holidays. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Repopulation/ Regeneration
Part No 3, Lesson No 2 Biology Repopulation/ Regeneration Also normal tissue repopulate - this is an important mechanism to reduce acute side effects from e.g. the irradiation of skin or mucosa Radiation schedules must allow sufficient regeneration time for acutely reacting tissues. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology The 4 Rs of radiotherapy: Influence on time between fractions, t, and overall treatment time, T Reoxygenation Redistribution Repair Repopulation (or Regeneration) Need minimum T Need minimum t Need minimum t for normal tissues Need to reduce T for tumour This slide is well suited for a longer discussion of the different effects - all these effects are obvious once understanding the problem. This slide leads also into the next section of the lecture: time effects. On the right side is shown the relevant R and on the left side the most important clinical consequence Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology The 4 Rs of radiotherapy: Influence on time between fractions, t, and overall treatment time, T Reoxygenation Redistribution Repair Repopulation (or Regeneration) Need minimum T Need minimum t Need minimum t for normal tissues Need to reduce T for tumor Cannot achieve all at once - Optimization of schedule for individual circumstances … unfortunately a choice is necessary. The course should help to make an informed decision. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

4. Time, dose and fractionation
Part No 3, Lesson No 2 Biology 4. Time, dose and fractionation Need to optimize fractionation schedule for individual circumstances Parameters: Total dose Dose per fraction Time between fractions Total treatment time After discussion of the four R’s a more explicit discussion of time effects is necessary. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Extension of LQ model to include time:
Part No 3, Lesson No 2 Biology Extension of LQ model to include time: E = - ln S = n * d (α + βd) - γT γ equals ln2/Tp with Tp the potential doubling time note that the γT term has the opposite sign to the α + βd term indicating tumour growth instead of cell kill With T = overall treatment time Tp = the potential doubling time which can be determined from cell biological experiments. The original LQ model without time effect was: E = - ln S = n * d (α + βd) The lecturer should point out that the time term gammaT has the opposite sign than the a/b term. Increasing the time increases the survival and NOT the cell kill. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

The potential doubling time
Part No 3, Lesson No 2 Biology The potential doubling time the fastest time in which a tumour can double its volume depends on cell type and can be of the order of 2 days in fast growing tumours can be measured in cell biology experiments requires optimal conditions for the tumour and is a worst case scenario Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Extension of LQ model to include time:
Part No 3, Lesson No 2 Biology Extension of LQ model to include time: E = - ln S = n * d (α + βd) - γT Including Tk ("kick off time") which allows for a time lag before the tumour switches to the fastest repopulation time: BED = (1 + d / (α/β)) * nd - (ln2 (T - Tk)) / αTp Evidence for the kick-off time is shown in the next slide. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Evidence for “kick off” time
Part No 3, Lesson No 2 Biology Evidence for “kick off” time This ‘classical’ figure by R Withers (1988) shows isoeffective total doses in 2Gy fractions as a function of overall treatment time. More dose is required if the treatment is prolonged (to counteract proliferation). However, it appears that after some 3 weeks of treatment the loss of treatment efficiency is greater, indicating a more rapidly proliferating tumor. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Use of the LQ model in external beam radiotherapy:
Part No 3, Lesson No 2 Biology Use of the LQ model in external beam radiotherapy: Calculate ‘equivalent’ fractionation schemes Determine radiobiological parameters Determine the effect of treatment breaks e.g. Do we need to give extra dose for the long weekend break? Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Calculation of equivalent fractionation schemes
Part No 3, Lesson No 2 Biology Calculation of equivalent fractionation schemes Assume two fractionation schemes are identical in biological effect if they produce the same BED BED = (1+d1/(α/β))n1d1 = (1+d2/(α/β))n2d2 This is obviously only valid for one tissue/tumour type with one set of alpha, beta and gamma values Example at the end of the lecture Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Brachytherapy Typically not a homogenous dose distribution Low dose rate treatment possible High dose rate treatments are typically given with larger fractions than external beam radiotherapy Pulsed dose rate somewhere in between All radiobiological modeling so far has been for external beam - what about brachytherapy…? It is important to note that brachytherapy dose distributions are characterized by large variations of dose even within the target volume - as such radiobiological evaluation is more difficult. More details on the schemes mentioned above are given in parts 6 and 11 Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

LQ model can be extended to brachytherapy
Part No 3, Lesson No 2 Biology LQ model can be extended to brachytherapy HDR with short high dose fractions can be handled very similarly to external beam radiotherapy However, the dose inhomogeneities inherent in brachytherapy (compare parts 6 and 11 of the course) make a good calculation difficult. Every different dose level will result in a different probability of cell kill - in practice this leads to the lowest dose in the target determining the outcome (no particular use in overdosing as all cells are already dead, however, missing one clonogenic cell due to low dose results in treatment failure). Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology LDR brachytherapy An extension of the LQ model to cover low dose rates with significant repair occurring during treatment Mathematics developed by R Dale (1985) Too complex for present course… Reference is: Dale RG. The application of the linear quadratic dose effect equation to fractionated and protracted radiotherapy. Brit. J Radiol 58: , 1985. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Brachytherapy LQ model allows BED calculation for brachytherapy comparison possible for external beam and brachytherapy adding of biologically effective doses possible Brachytherapy has the potential to minimize the dose to normal structures - probably still the most important factor is good geometry of an implant The ability to use one model for the calculation of biological effective dose in both brachytherapy and external beam radiotherapy allows to compare different approaches and add doses from combined treatments. This has recently been used also the other way round to calculate a/b ratios for tumours in the case of prostate cancer where 125-I seed implants, HDR brachyhterapy and external beam radiotherapy are compared. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

However, caution is necessary
Part No 3, Lesson No 2 Biology However, caution is necessary All models are just models The radiobiological parameters are not well known Parameters for a population of patients may not apply to an individual patient This is a very important qualifier. Clinical judgement and experience of an appropriately qualified radiation oncologist are needed to interpret the models and check if they are applicable in an individual case. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

A note on different radiation qualities
Part No 3, Lesson No 2 Biology A note on different radiation qualities Not only in radiation protection is there a different effectiveness of different radiation types - however: The effect of concern is different The Relative Biological Effectiveness (RBE values) is different - e.g. for neutrons in therapy RBE is about 3 The effect of fractionation may be VERY different Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology The picture shows the ionisation events due to a photon of 1MeV (left) and a neutron of the same energy (right). Both pictures reflect a dose of 10mGy, however, in the case of neutrons the ionisation events are much closer together, making repair more difficult and the radiation more effective. Adapted from Marco Zaider (2000) Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Comparison of dose response of neutrons and photons
Part No 3, Lesson No 2 Biology Comparison of dose response of neutrons and photons The microscopic picture of the previous slide is reflected also in the dose response curves of neutrons and photons in the case of bladder cancer. The vertical axis shows effect (100 is complete tumor response) and the horizontal axis is dose. The relative biological effectiveness of neutrons is 3. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Summary Radiobiology is essential to understand the effects of radiotherapy It is also important for radiation protection of the patient as it allows minimization of the radiation effects in healthy tissues There are models which allow to estimate the effect of a given radiotherapy schedule Caution is necessary when applying a model to an individual patient - clinical judgement should not be overruled Let’s summarize the main subjects we did cover in this session. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Where to Get More Information
Part No 3, Lesson No 2 Biology Where to Get More Information Other sessions References: Steel G (ed): Radiobiology, 2nd ed. 1997 Hall E: Radiobiology for the radiologist, 3rd ed. Lippincott, Philadelphia 1988 Withers R. The four Rs of radiotherapy. Adv. Radiat. Biol. 5: ; 1975 Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Any questions? Part No 3, Lesson No 2 Biology
IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Question: Please calculate the dose per fraction in a five fraction treatment for a palliative radiotherapy treatment which results in the same biologically effective dose to the tumour as a single fraction of 8Gy (assume a/b = 20Gy (tumour) or 2Gy (spinal cord)). Assuming no time effects (ie. Time between fractions is large enough to allow full repair and the overall treatment time is short enough to prohibit significant repopulation during the treatment) the biologically effective dose (BED) of the treatment schedules can be calculated as BED = nd (1 + d/(a/b)) with n number of fractions, d dose per fraction and a/b the alphabeta ratio BED (tumour, single fraction) = 1 * 8 (1 + 8/20) = 11.2Gy to get a similar BED in five fractions for the tumour one needs to deliver 2Gy per fraction (BED = 11Gy) BED (spinal cord, single fraction) = 1 * 8 (1 + 8/2) = 40Gy to get a similar BED in five fractions for the tumour one needs to deliver 3.1Gy per fraction (BED = 39.5Gy) This example illustrates how much more sensitive late reacting normal tissue is to fractionation. The single dose of 8Gy is nearly 4 times more toxic to spinal cord than to a tumour. IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Answer (part 1) Assuming no time effects (i.e. time between fractions is large enough to allow full repair and the overall treatment time is short enough to prohibit significant repopulation during the treatment) the biologically effective dose (BED) of the treatment schedules can be calculated as BED = nd (1 + d/(a/b)) with n number of fractions, d dose per fraction and a/b the alphabeta ratio BED (tumour, single fraction) = 1 * 8 (1 + 8/20) = 11.2Gy Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

Part No 3, Lesson No 2 Biology Answer (part 2) to get a similar BED in five fractions for the tumour, one needs to deliver 2Gy per fraction (BED = 11Gy) BED (spinal cord, single fraction) = 1 * 8 (1 + 8/2) = 40Gy to get a similar BED in five fractions for the spinal cord, one needs to deliver 3.1Gy per fraction (BED = 39.5Gy) This example illustrates how much more sensitive late reacting normal tissue is to fractionation. The single dose of 8Gy is nearly 4 times more toxic to spinal cord than to a tumour. Part 3, lecture 2: High doses in radiation therapy IAEA Training Material: Radiation Protection in Radiotherapy

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