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Radiation Protection in Radiotherapy Part 3 Biological Effects Lecture 2: High Doses in Radiation Therapy IAEA Training Material on Radiation Protection.

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Presentation on theme: "Radiation Protection in Radiotherapy Part 3 Biological Effects Lecture 2: High Doses in Radiation Therapy IAEA Training Material on Radiation Protection."— Presentation transcript:

1 Radiation Protection in Radiotherapy Part 3 Biological Effects Lecture 2: High Doses in Radiation Therapy IAEA Training Material on Radiation Protection in Radiotherapy

2 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy2 Overview l Radiobiology is of great importance for radiotherapy. It allows the optimization of a radiotherapy schedule for individual patients in regards to: n Total dose and number of fractions n Overall time of the radiotherapy course n Tumour control probability (TCP) and normal tissue complication probability (NTCP)

3 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy3 Objectives l To understand the radiobiological background of radiotherapy l To be familiar with the concepts of tumour control probability and normal tissue complication probability l To be aware of basic radiobiological models which can be used to describe the effects of radiation dose and fractionation

4 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy4 Contents 1. Basic Radiobiology 2. The linear quadratic model 3. The four ‘R’ s of radiotherapy 4. Time and fractionation

5 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy5 1. Basic Radiobiology l The aim of radiotherapy is to kill tumor cells and spare normal tissues l In external beam and brachytherapy one inevitably delivers some dose to normal tissue patient tumor Beam 3 Beam 2 Beam 1 Brachytherapy sources

6 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy6 Basic Radiobiology: target l 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. l 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), … l Several pathways to tumour sterilization exist (e.g. mitotic cell death, apoptosis (= programmed cell death), …)

7 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy7 Survival curves

8 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy8 Radiobiology: tumor l Irradiation kills cells l Different mechanisms of cell kill l Different radio-sensitivity of different tumours l Reduction in size makes tumour n better oxygenated n grow faster

9 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy9 Radiobiology: micrometastasis l Tumours may spread first through adjacent tissues and lymph nodes nearby l Need to irradiate small deposits of clonogenic cells early l Less dose required as each fraction of radiation reduces the number of cells by a certain factor

10 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy10 The target in radiotherapy l The bulk tumour n may be able to distinguish different parts of the tumour in terms of radiosensitivity and clonogenic activity l Confirmed tumour spread l Potential tumour spread

11 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy11 Reminder l Palpable tumour (1cm 3 ) = 10 9 cells !!! l Large mass (1kg) = cells - need three orders of magnitude more cell kill l Microscopic tumour, micrometastasis = around 10 6 cell - need less dose

12 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy12 Radiobiology: normal tissues l Sparing of normal tissues is essential for good therapeutic outcome l The radiobiology of normal tissues may be even more complex as the one of tumours: n different organs respond differently n there is a response of a cell organization not just of a single cell n repair of damage is in general more important

13 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy13 Different tissue types l Serial organs (e.g. spine) l Parallel organs (e.g. lung)

14 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy14 Different tissue types l Serial organs (e.g. spine) l Parallel organs (e.g. lung) Effect of radiation on the organ is different

15 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy15 Volume effects l The more normal tissue is irradiated in parallel organs n the greater the pain for the patient n the more chance that a whole organ fails l Rule of thumb - the greater the volume the smaller the dose should be l In serial organs even a small volume irradiated beyond a threshold can lead to whole organ failure (e.g. spinal cord)

16 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy16 Classification of radiation effects in normal tissues l Early or acute reactions n Skin reddening, erythema n Nausea n Vomiting n Tiredness l Occurs typically during course of RT or within 3 months l Late reactions n Telangectesia n Spinal cord injury, paralysis n Fibrosis n Fistulas l Occurs later than 6 months after irradiation

17 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy17 Classification of radiation effects in normal tissues l Early or acute reactions l Late reactions Late effects can be a result of severe early reactions: consequential radiation injury

18 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy18 Late effects l Often termed complications (compare ICRP report 86) l Can occur many years after treatment l Can be graded - lower grades more frequent

19 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy19 A comment on vascularisation l Blood vessels play a very important role in determining radiation effects both for tumours and for normal tissues. l Vascularisation determines oxygenation and therefore radiosensitivity l Late effects may be related to vascular damage

20 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy20 Summary of radiation effects l Target in radiotherapy is bulk tumour and confirmed and/or suspected spread l Need to know both effects on tumour and normal tissues l Normal tissues need to be considered as a whole organ l Radiation effects are complex - detailed discussion of radiation effects is beyond the scope of the course l Models are used to reduce complexity and allow prediction of effects...

21 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)

22 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy22 Radiobiological models l Many models exist l Based on clinical experience, cell experiments or just the beauty or simplicity of the mathematics l 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.

23 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy23 2. The Linear Quadratic Model l Cell survival: single fraction: S = exp(-(αD + βD 2 )) (n fractions of size d: S = exp(- n (αd + βd 2 )) l Biological effect: E = - ln S = αD + βD 2 E = n (αd + βd 2 ) = nd (α + βd) = D (α + βd)

24 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy24 Biological effectiveness E/α = BED = (1 + d / (α/β)) * D = RE * D l l BED = biologically effective dose, the dose which would be required for a certain effect at infinitesimally small dose rate (no beta kill) l l RE = relative effectiveness

25 Quick question??? What is the physical unit for the a/b ratio?

26 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy26 BED useful to compare the effect of different fractionation schedules l Need to know a/b ratio of the tissues concerned. l a/b typically lower for normal tissues than for tumour

27 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy27 The linear quadratic model

28 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy28 The linear quadratic model Alpha determines initial slope Beta determines curvature

29 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy29 Rule of thumb for a/b ratios l Large a/b ratios l a/b = 10 to 20 n Early or acute reacting tissues n Most tumours l Small a/b ratio l a/b = 2 n Late reacting tissues, e.g. spinal cord n potentially prostate cancer

30 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy30 The effect of fractionation

31 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy31 Fractionation l Tends to spare late reacting normal tissues - the smaller the size of the fraction the more sparing for tissues with low a/b l Prolongs treatment

32 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy32 A note of caution l This is only a model l Need to know the radiobiological data for patients l Important assumptions: n n There is full repair between two fractions n n There is no proliferation of tumour cells - the overall treatment time does not play a role.

33 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy33 3. The 4 Rs of radiotherapy l R Withers (1975) l l R eoxygenation l l R edistribution l l R epair l l R epopulation (or Regeneration)

34 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy34 Reoxygenation l Oxygen is an important enhancement for radiation effects (“Oxygen Enhancement Ratio”) l The tumour may be hypoxic (in particular in the center which may not be well supplied with blood) l One must allow the tumour to re-oxygenate, which typically happens a couple of days after the first irradiation

35 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy35 Redistribution l Cells have different radiation sensitivities in different parts of the cell cycle l Highest radiation sensitivity is in early S and late G2/M phase of the cell cycle G1 S (synthesis) M (mitosis) G2

36 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy36 Redistribution l 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 l One must consider this when irradiating cells with breaks of few hours.

37 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy37 Repair l All cells repair radiation damage l This is part of normal damage repair in the DNA l 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!) l The half time for repair, t r, is of the order of minutes to hours

38 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy38 Repair l It is essential to allow normal tissues to repair all repairable radiation damage prior to giving another fraction of radiation. l This leads to a minimum interval between fractions of 6 hours l Spinal cord seems to have a particularly slow repair - therefore, breaks between fractions should be at least 8 hours if spinal cord is irradiated.

39 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy39 Repopulation l Cell population also grows during radiotherapy l For tumour cells this repopulation partially counteracts the cell killing effect of radiotherapy l The potential doubling time of tumours, T p (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

40 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy40 Repopulation l 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”, T k ) repopulation accelerates. l Repopulation must be taken into account when protracting radiation e.g. due to scheduled (or unscheduled) breaks such as holidays.

41 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy41 Repopulation/ Regeneration l Also normal tissue repopulate - this is an important mechanism to reduce acute side effects from e.g. the irradiation of skin or mucosa l Radiation schedules must allow sufficient regeneration time for acutely reacting tissues.

42 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy42 The 4 Rs of radiotherapy: Influence on time between fractions, t, and overall treatment time, T l l R eoxygenation l l R edistribution l l R epair l l R epopulation (or Regeneration) l Need minimum T l Need minimum t l Need minimum t for normal tissues l Need to reduce T for tumour

43 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy43 The 4 Rs of radiotherapy: Influence on time between fractions, t, and overall treatment time, T l l R eoxygenation l l R edistribution l l R epair l l R epopulation (or Regeneration) l Need minimum T l Need minimum t l Need minimum t for normal tissues l Need to reduce T for tumor Cannot achieve all at once - Optimization of schedule for individual circumstances

44 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy44 4. Time, dose and fractionation l Need to optimize fractionation schedule for individual circumstances l Parameters: n Total dose n Dose per fraction n Time between fractions n Total treatment time

45 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy45 Extension of LQ model to include time: E = - ln S = n * d (α + βd) - γT l l γ equals ln2/T p with T p the potential doubling time l l note that the γT term has the opposite sign to the α + βd term indicating tumour growth instead of cell kill

46 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy46 The potential doubling time l l the fastest time in which a tumour can double its volume l l depends on cell type and can be of the order of 2 days in fast growing tumours l l can be measured in cell biology experiments l l requires optimal conditions for the tumour and is a worst case scenario

47 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy47 Extension of LQ model to include time: E = - ln S = n * d (α + βd) - γT Including T k ("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 - T k )) / αT p

48 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy48 Evidence for “kick off” time

49 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy49 Use of the LQ model in external beam radiotherapy: l Calculate ‘equivalent’ fractionation schemes l Determine radiobiological parameters l Determine the effect of treatment breaks n e.g. Do we need to give extra dose for the long weekend break?

50 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy50 Calculation of equivalent fractionation schemes l Assume two fractionation schemes are identical in biological effect if they produce the same BED BED = (1+d 1 /(α/β))n 1 d 1 = (1+d 2 /(α/β))n 2 d 2 This is obviously only valid for one tissue/tumour type with one set of alpha, beta and gamma values l Example at the end of the lecture

51 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy51 Brachytherapy l Typically not a homogenous dose distribution n Low dose rate treatment possible n High dose rate treatments are typically given with larger fractions than external beam radiotherapy n Pulsed dose rate somewhere in between

52 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy52 LQ model can be extended to brachytherapy l HDR with short high dose fractions can be handled very similarly to external beam radiotherapy l However, the dose inhomogeneities inherent in brachytherapy (compare parts 6 and 11 of the course) make a good calculation difficult.

53 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy53 LDR brachytherapy l An extension of the LQ model to cover low dose rates with significant repair occurring during treatment l Mathematics developed by R Dale (1985) l Too complex for present course…

54 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy54 Brachytherapy l LQ model allows BED calculation for brachytherapy n comparison possible for external beam and brachytherapy n adding of biologically effective doses possible l Brachytherapy has the potential to minimize the dose to normal structures - probably still the most important factor is good geometry of an implant

55 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy55 However, caution is necessary l All models are just models l The radiobiological parameters are not well known l Parameters for a population of patients may not apply to an individual patient

56 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy56 A note on different radiation qualities l Not only in radiation protection is there a different effectiveness of different radiation types - however: n The effect of concern is different n The Relative Biological Effectiveness (RBE values) is different - e.g. for neutrons in therapy RBE is about 3 n The effect of fractionation may be VERY different

57 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy57 Adapted from Marco Zaider (2000)

58 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy58 Comparison of dose response of neutrons and photons

59 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy59 Summary l Radiobiology is essential to understand the effects of radiotherapy l It is also important for radiation protection of the patient as it allows minimization of the radiation effects in healthy tissues l There are models which allow to estimate the effect of a given radiotherapy schedule l Caution is necessary when applying a model to an individual patient - clinical judgement should not be overruled

60 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy60 Where to Get More Information l Other sessions l References: n Steel G (ed): Radiobiology, 2nd ed n Hall E: Radiobiology for the radiologist, 3rd ed. Lippincott, Philadelphia 1988 n Withers R. The four Rs of radiotherapy. Adv. Radiat. Biol. 5: ; 1975

61 Any questions?

62 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)).

63 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy63 Answer (part 1) l 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 l BED = nd (1 + d/(a/b)) with n number of fractions, d dose per fraction and a/b the alphabeta ratio l BED (tumour, single fraction) = 1 * 8 (1 + 8/20) = 11.2Gy

64 Radiation Protection in RadiotherapyPart 3, lecture 2: High doses in radiation therapy64 Answer (part 2) l to get a similar BED in five fractions for the tumour, one needs to deliver 2Gy per fraction (BED = 11Gy) l BED (spinal cord, single fraction) = 1 * 8 (1 + 8/2) = 40Gy l to get a similar BED in five fractions for the spinal cord, one needs to deliver 3.1Gy per fraction (BED = 39.5Gy) l 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.


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