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BIOLOGICALLY EFFECTIVE DOSE (BED)
A method has been proposed for using the α/β ratio for calculating
the change in tumour dose necessary to achieve an equal response
in tissue when the dose per fraction is varied
Note: this calculation amounts only for the effect of repair of
sublethal injury (under normal conditions can be repaired in hours
unless additional sublethal damage is attained)
BED = nd[1+d/ (α/β)]
where d = dose per fraction (Gy), n = number of fraction
BED = total dose x relative effectiveness ( has unit of dose)
If total dose (nd or D) is kept constant, the BED will increase if dose
per fraction is increased](https://image.slidesharecdn.com/radiobiologycont-250520131125-227d8624/75/Radiobiology-Continue-for-Radiographers-pptx-41-2048.jpg)
![45
BED for tumour proliferation
correction factor
The BED received by a uniformly irradiated tissue which is
concurrently repopulating is calculated as:
BED = nd[1+d/ (α/β)] – K (T-Tdelay)
Where T = overall treatment time,
Tdelay = the time lag (from the beginning of treatment) before tumour
repopulation begins to occur and is tumour specific
K, in units of Gy per day, is the daily BED equivalent of repopulation
and is tumour specific](https://image.slidesharecdn.com/radiobiologycont-250520131125-227d8624/75/Radiobiology-Continue-for-Radiographers-pptx-45-2048.jpg)
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- 1.
- 2. 2 OUTLINE Survival curve Normal Tissue Radiobiology LQ model and Dose Response BED
- 3. 3 Survival curve formammalian cells Graphical parameters describing shape of cell Survival curve n- EXTRAPOLATION NUMBER Do- RECPROCAL OF FINAL SLOPE Dq- DEFINES SIZE OF SHOULDER REGION
- 4. 4 Significance of cellsurvival curves The radiosensitivities for normal tissues can be illustrated by plotting surviving fraction vs dose resulting from clonogenic assays There is a substantial range of sensitivities, with shoulder width being the main variable Single dose survival curves have been measured for many established cell lines grown in-vitro
- 5. 5 Significance of cellsurvival curves These survival curves seem to show relatively small differences between the intrinsic radiosensitivities of different cell populations, in terms of Do >> In-vitro cell survival curves give an indication of the intrinsic radiosensitivity of a cell population – Do >> The Do of the x-ray survival curve falls in the range of 1 -2Gy These Do values provide some indication of the radiosensitivity of the different cell populations
- 6. 6 Significance of cellsurvival curves However, they only provide a measure of the final slope of the curve, usually over a dose range in excess of about 20Gy In addition, they provide little explanation for the wider differences in the radiosensitivity of both tumours & normal tissue that are found in clinical practice There is a much larger variation in values for Dq, which reflects the size of the shoulder region There is also evidence for a wide variation in the extrapolation number, n, for human tumour cell populations The values range from 1.1 for Burkitt lymphoma to 163 for adenocarcinoma of the rectum
- 7. 7 Significance of cellsurvival curves An alternative parameter of radiosensitivity has been suggested, and is perhaps more relevant to the doses used in fractionated radiotherapy & would take into account the variation in shoulder size The surviving fraction is noted in the 2Gy level & this is then used as a basis for comparison btw different human tumours It was found that the survival levels varied btw 0.18 & 0.77 This is more than a four – fold range in ‘radiosensitivity’ & would seem to be much more in accord with clinical experience
- 8. 8 Human tumour-cell survival Survivingfraction at 2Gy varies btw 0.18 & 0.77, more than a four-fold range in radiosensitivity (table below) Tumour type Do (Gy) N Survival at 2Gy Melanoma 1 40 0.77 Melanoma 1.05 23 0.61 Colon 1.00 5.5 0.4 Colon 0.88 30 0.57 Rectum 0.7 163 0.54 Cervix 1.3 3.8 0.48 Cervix 1.07 4.4 0.42 Pancreas 1.00 1.5 0.22 Burkitt 1.25 1.1 0.18
- 9. 9 Radiation Damage LethalDamage >> Irreversible, irreparable, leading to cell death Sublethal Damage (SLD) >> under normal conditions can be repaired in hours unless additional sublethal damage is attained
- 10. 10 Sublethal Damage Whena dose of radiation is divided into 2 equal doses separated by an interval of time, the surviving fraction of cells was larger than if the same total dose were given as a single dose Split dose experiments illustrate SLD Increase in survival is due to sublethal damage (SLD) repair
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- 13. 13 Sublethal Damage Degreeof sublethal damage agrees well with size of shoulder on cell survival curve Broad Shoulder: relatively large amount of SLD repair Narrow shoulder: relatively lower amount of SLD repair Correlation with linear-quadratic model in terms of α/β
- 14.
- 15. 15 Normal tissue structure Differentiation >> a differentiated cell is one that is specialised functionally or morphologically Stem cell population >> relatively undifferentiated Transit cell population >> may or may not divide in transit Static cell population >> fully differentiated
- 16. 16 Types of mammaliancell Epithelial tissue: cells that grow into sheets that cover organs & line cavities e.g. skin cuboidal cells lining ducts from glands such as salivary glands, columnar cells lining digestive tract Connective tissue cells form the structural units of the body, e.g. bone cartilage, tendon Muscular tissue cells are arranged in sheets or bundles Nervous tissue includes brain, spinal cord & nerves. E.g. neuron is an elongated cell with a very specialised function Blood cells e.g. RBCs transport haemoglobin, WBCs produced in the bone marrow deal with infections, lymphocytes are also involved in the body defence system
- 17. 17 Cell populations &kinetic properties No mitosis No renewal Low mitotic index Little or no cell renewal Frequent mitosis Cell renewal CNS Sense organs Adrenal medulla Liver Thyroid Vascular endothelium Connective tissue Epidermis Intestine epithelium Bone marrow Gonads
- 18. 18 Radiation Pathology Theresponse of a tissue or organ to radiation depends primarily on 2 factors: 1. Inherent sensitivity 2. Population kinetics Tissues composed of highly differentiated cells performing specialised functions exhibit little or no mitotic activity therefore exhibit relative radioresistace In a self renewing tissue loss of stem cells occurs after relatively low dose (a few Gy) The time interval btw irradiation & its expression in tissue damage is variable
- 19. 19 Normal tissues-tolerance Totaldose can be tolerated depends on the volume of tissue irradiated Tolerance dose is that dose which produces an acceptable probability of a treatment complication The spatial arrangement of the FSUs is critical
- 20. 20 Normal tissues-functional subunits Radiation tolerance depends on the ability of the clonogenic cells to regenerate producing mature cells structured to maintain organ function Tissues can be thought of as consisting of functional subunits (FSUs) In some tissues, the FSUs are discrete, anatomically delineated structures whose relationship to tissue function is clear, e.g. the nephron in the kidney, the lobule in the lung In other tissues, the FSUs have no clear anatomical demarcation, e.g. the skin, the mucosa & the spinal cord
- 21. 21 Normal tissues-volume effect Where the FSUs are arranged serially, the integrity of each is critical to organ function, e.g. the spinal cord, death of critical cells in any one segment will result in complete failure of the organ Tissues in which FSUs are not arranged serially tend not to show a volume effect at lower levels of injury Healing can occur from surviving clonogens scattered throughout the treatment volume, e.g. skin, mucosa However, although the severity of a skin reaction is relatively independent of the area irradiated, how this injury is tolerated is not independent of the area irradiated So clinically there will in fact still be a volume effect
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- 23. 23 Cancer Cancer ischaracterised by a disorderly proliferation of cells that can invade adjacent tissues & spread via the lymphatic system or blood vessels to other parts of the body Aim of radiotherapy is to deliver enough radiation to the tumour to destroy it without irradiating normal tissue to a dose that will lead to serious complications (morbidity)
- 24. 24 The Molecular BiologicalHallmark of Cancer There is simple evidence to support the hypothesis that human tumours arise as part of a sequential multi-step process Each step reflecting the accumulation of genetic alterations that confer a survival advantage on the evolving malignant cell
- 25. 25 The Molecular BiologicalHallmark of Cancer
- 26.
- 27. 27 Dose Response Curve Plot of a biological effect observed (e.g. tissue response) again the dose given is called a dose response curve Dose response may refer to: >> Clonogenic end points i.e. cell survival >> Functional end points Generally, as the dose increases so does the effect
- 28. 28 Dose Response ClonogenicAssay - The endpoints observed depends directly on the reproductive integrity of individual cells – cell survival curves Dose response relationships - Can be obtained repeatedly & each quantitative but that depend on Functional Endpoints, such as skin reactions - A dose-response curve can be inferred for tissue in which it cannot be observed directly Dose-Response dependent on cell & tissue type
- 29. 29 Dose Response Relationship– Acute & late effects Acute & late effects tissues exhibit differing responses to a given dose of radiation & the cells involved exhibit different cell survival shapes particularly in the shoulder region When the cell survival (or dose response) curve is studied late- responding tissues have a more curved dose-response relationship than for acute or early responding tissues Differences in shoulder shape of the underlying dose-response curves due to the significance of the component of single-hit killing & repair Broader shoulder indicates repair of sublethal damage This difference is reflected in the linear-quadratic relationship for these tissues
- 30. 30 Linear Quadratic Model Produces a continuously bending survival curve, which has the expected initial slope but which never becomes exponential, even at high doses This model has been applied to data relating to the tolerance of normal tissues to various alternative fractionation regimes used in radiotherapy
- 31. 31 Dose Response Linear Quadratic- Relationship Equation describing survival as a function of dose S = e-αD-βD S is surviving fraction, D is single dose (or dose per fraction, d) Coefficients α & β from this equation describe individual cell type survival curves Ratio of coefficients α/β important in radiotherapy, indicating the response of tissue to a radiation
- 32. 32 Dose Response Relationship α/βRatio In general, α/β is larger (about 10 Gy) for acute effect than for late effects (about 2 Gy) α represents the linear (i.e 1st order dose dependent) component of cell killing – single hit β represents the quadratic ( i.e 2nd order dose dependent) component of cell killing – repairable component of cell killing α/β ratio has units of dose & is the dose at which cell killing by the linear and quadratic dose components are equal i.e α D=β D2 D=α/β
- 33. 33 Dose Response Relationship α/βRatio A high α/β ratio imples a long linear slope A low α/β ratio indicates a curvier survival response at low doses These differences in acute & late effect tissue α/β ratios & dose response curves significantly reflects the response of these tissues to fractionated radiotherapy
- 34. 34 Dose Response Relationshipα/β Ratio
- 35. 35 Inferring the α/βRatio The parameters of the dose response curve for any normal tissue system for which functional endpoint can be observed may be inferred by performing a multifractional experiment For example, an experiment in which skin reaction is scored - assumptions: linear quadratic model applies - each dose produces the same biological effect - full repair of SLD occurs btw dose fractions - no cell proliferation occurs btw fractions
- 36. 36 Linear-Quadratic Model L-Qapproach is a biological model of radiation action which was first proposed over 60 yrs ago Based on a mechanistic analysis of chromosomal- aberration induction Distinction between linear & quadratic components in terms of their dependence on dose fractionation Proposed basic lesion responsible for radiation-induced cell death is the dicentric exchange-type chromosomal aberration
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- 38. 38 Linear-Quadratic Model – mechanisticbasis If a single track of radiation causes DNA damage to 2 chromosomal sites which then misrepair to form an exchange-type chromosomal aberration, the aberration yield will be linear with dose & independent of dose protraction If 2 independent tracks of radiation produce 2 DNA damage sites which subsequently interact to form an aberration, then the yield ( and log survival) will vary as dose squared, & will depend on fractionation – because the first damage site may have time for repair before the 2nd is formed
- 39. 39 BIOLOGICALLY EFFECTIVE DOSE(BED) Biological effectiveness observed after administration of a certain absorbed dose depends on the time-dose-fractionation pattern used to deliver it BED is commonly used for isoeffective calculation BED is a measure of the true biological dose delivered by a particular combination of dose per fraction & total dose to a particular tissue characterized by a specific α/β ratio α/β ratio is the dose response relationship ratio
- 40. 40 BIOLOGICALLY EFFECTIVE DOSE(BED) In general, α/β is larger (about 10 Gy) for acute effect than for late effects (about 2 Gy) Α represents the linear (i.e 1st order dose dependent) component of cell killing – single hit Β represents the quadratic ( i.e 2nd order dose dependent) component of cell killing – repairable component of cell killing α/β ratio has units of dose & is the dose at which cell killing by the linear and quadratic dose components are equal i.e α D=β D2 D=α/β
- 41. 41 BIOLOGICALLY EFFECTIVE DOSE(BED) A method has been proposed for using the α/β ratio for calculating the change in tumour dose necessary to achieve an equal response in tissue when the dose per fraction is varied Note: this calculation amounts only for the effect of repair of sublethal injury (under normal conditions can be repaired in hours unless additional sublethal damage is attained) BED = nd[1+d/ (α/β)] where d = dose per fraction (Gy), n = number of fraction BED = total dose x relative effectiveness ( has unit of dose) If total dose (nd or D) is kept constant, the BED will increase if dose per fraction is increased
- 42. 42 BIOLOGICALLY EFFECTIVE DOSE(BED) So we can compute a biological effective dose for α/β ratio for both early and late effects a given fractionation regime For a specific tissue, if the calculated BED is higher for one treatment regime than another then the fractionation regime is more effective BED is a useful term when comparing dose/fractionation patterns for a specific tissue of interest Note: there is a relatively wide range of α/β due to the natural variation of α and β in human populations Note: the use of smaller α/β ratios result in larger BED values for a given dose/fractionation pattern
- 43. 43 BED FOR TUMOURCALCULATION The numerical range of α/β ratios is wider in tumours & data are lacking for many specific tumour types A repopulation correction factor should be included in the case of tumours that contain rapidly proliferating clonogenes, for which there are several possible patterns of repopulation to consider Vary from accepted values of 10-30Gy for squamous cell cancers to much lower values of 4-5Gy in breast cancer Slower growing tumours, such as prostate, appear to have very small ratios (0.8- 2.5Gy) For many tumour types there are no established generic values In general, for tumour that have high ratio values, the total dose and the fraction size together determine the outcome It may be prudent to perform multiple BED calculations in order to achieve some general conclusion about which fraction policy to chose.
- 44. 44 TUMOUR KINETICS Tpot- Potentialtumour doubling time Tpot is a measure of the rate of increase of cells capable of continued proliferation & determines the outcome of a radiotherapy treatment protocol & is the time during which the tumour would be expected to double based on the cell cycle time & the growth fraction Tumours with a short Tpot may repopulate if fractionation is extended over too long a period Tpot can be estimated experimentally from studies on biopsy cell samples. This provides an average Tpot. Tpot may have a value of 2 to 25 days with a median of about 5 days A mathematical correction may be applied to the linear quadratic equation to allow for tumour proliferation
- 45. 45 BED for tumourproliferation correction factor The BED received by a uniformly irradiated tissue which is concurrently repopulating is calculated as: BED = nd[1+d/ (α/β)] – K (T-Tdelay) Where T = overall treatment time, Tdelay = the time lag (from the beginning of treatment) before tumour repopulation begins to occur and is tumour specific K, in units of Gy per day, is the daily BED equivalent of repopulation and is tumour specific
- 46. 46 BED CALCULATIONS Thefollowing data is for questions 1 and 2. Squamous cell H&N Cancer Acute responding normal tissue Late Responding Normal tissue 10Gy 10Gy 3Gy Tdelay 28 days N/A N/A K 0.9Gy/day (after Tdelay) 0.1Gy/day (up to Tdelay) N/A N/A
- 47. 47 BED CALCULATIONS Regime A60Gy total dose 25 fractions 32 days overall Regime B 65Gy total dose 30 fractions 39 days overall Regime C 55Gy total dose 25 fractions 25 days overall
- 48. 48 BED CALCULATIONS 1.Assume the patient starts treatment on a Monday and is treated Monday to Friday each week. a) For treatment regime A, calculate the intended BED for this Tumour and for the Acute and Late responding normal tissues. b) For treatment regime B, calculate the intended BED for this Tumour and for the Acute and Late responding normal tissues. c) Compare the two regimes in terms of biological effectiveness for tumour control, acute and late normal tissue damage. Discuss which regime would be the regime of choice based on the BED calculations and taking into account tumour, acute and late responding normal tissues.
- 49. 49 BED CALCULATIONS 2.Assume the patient starts treatment on a Monday and is treated Monday to Friday each week. a) For Head and Neck 3DCRT Regime C is used. Calculate the intended BED for this Tumour and for the Acute and Late responding normal tissues. b) For Head and Neck Cancer VMAT Regime B is used. Calculate the intended BED for this Tumour and for the Acute and Late responding normal tissues. c) Compare the two regimes in terms of biological effectiveness for tumour control, acute and late normal tissue damage, stating which regime would be the regime of choice based on the BED calculations. d) Are there any other factors, from a non-radiobiological perspective, that could influence the decision on which regime to choose?