Basic Clinical Radiobiology Part 2 PDF

Presented by: An Introduction to clinical Radiobiology Dr Heather Lawrence. Senior Part 2 Lecturer: Radiotherap Code: RN-JS-OQ y and Oncology Cell survival and tumour response Most of the damage to cells caused by radiation is repaired a few hours after i...

Presented by: An Introduction to clinical Radiobiology Dr Heather Lawrence. Senior Part 2 Lecturer: Radiotherap Code: RN-JS-OQ y and Oncology Cell survival and tumour response Most of the damage to cells caused by radiation is repaired a few hours after irradiation. Repair: The process by which the function of the macromolecules is restored. Recovery: an increase in cell survival or a reduction in the extent of radiation damage to a tissue when sufficient time is allowed for this to occur. Tolerance: refers to the amount of radiation that tissues can receive and still remain functional. The dose prescribed in radiotherapy is limited by the tolerance of the surrounding normal tissue and not by the tumour. Therapeutic radio/window: the difference in dose between the probability of tumour control and normal tissue tolerance. Tumour control probability (TCP) for a given dose Normal tissue complication probability (NTCP) Tumour radiobiology basics Tumours, like normal tissues have a parenchymal component (tumour cells) and a stromal component (blood vessels, lymphatic vessels, connective and nerve tissue). The parenchymal component has 4 main subpopulations of cells : Group 1 : Well-oxygenated, viable and actively proliferating Group 2 : Well oxygenated, viable but not proliferating Group 3 : Hypoxic but viable Group 4: Anoxic and necrotic Tumour radiobiology Tumour growth is unorganised compared to that of normal tissue. Tumours tend to outgrow their vascular supply. A gradient of oxygen variability across the tumour results. Parts of the tumour therefore become anoxic and are unable to proliferate. They have no impact on clinical outcome. The hypoxic fraction of the tumour are the most radioresistant component and could be responsible for regrowth of the tumour after radiotherapy. Tumour growth (doubling time) depends on 3 things: Cell cycle time of the proliferating cells The size of the growth fraction The degree of cell loss from the tumour Radiosensitivity and radiocurability All of this means that tumours, just like normal tissue vary in their sensitivity to radiation. E.G a curative dose for a seminoma can be as little as 30Gy but a curative dose for a glioblastoma will be >80Gy The difference in the repair capability of tumours to radiation damage may explain this difference. The importance of preserving the function of normal tissue is expressed as a tolerance dose: A dose of radiation delivered by a standard fractionation schedule that will cause a minimum (5%) or a maximum (50%) complication rate within 5 years. TD5/5 or TD50/5 Time-Dose fractionation Radiation therapy delivers a high dose to the treatment area by diving the dose into treatment fractions. The total dose, the size of the fraction, the number of fractions and the overall treatment time is determined by the sensitivity of the tumour and the tolerance of the surrounding normal tissue. However, biologically, fractionated doses are less effective in causing cell death than a single high dose. So, a higher dose is needed to produce the same biologic response than would be needed if the dose was given as a single dose. So why do we fractionate radiotherapy treatments??? The 5 R’s of radiotherapy Repair Reassortment Repopulation Reoxygenation Radiosensitivity Repair Refers to the repair of sub-lethal damage. Helps to spare normal tissue from RT damage. Repair of SLD is oxygen dependent, so tumours in general have a limited ability to repair SLD. Taken from: https://radiologykey.com/11-radiation-treatment-of-cancer/ Reassortment / Redistribution Cells that survive a first dose of radiation will tend to be in a more radioresistant phase of the cell cycle and within a few hours, they may progress to a more sensitive phase of the cell cycle Repopulation During a fractionated schedule, cells that survive irradiation may proliferate and will increase the number of cells that must be killed to achieve a good therapeutic outcome. This repopulation of the clonogenic cells will be faster in tissues and tumours with fast doubling times. Not applicable therefore to late responding normal tissue! Necessary in normal tissue so that tolerance is not exceeded. Contributes to tumour regrowth during and after treatment. Reoxygenation Hypoxic tumour cells reoxygenate during fractionated radiotherapy. Little effect on normal tissue as they are already well oxygenated Radiosensitivity Repair and repopulation will make tissue more resistant to a second dose of radiation BUT reassortment and reoxygenation will make it more sensitive! The 4 factors combined modify the response of tissues and the tumour to fractionated radiotherapy and explain the shape of the isoeffect curves The steepness and curvature of the lines are explained by the The α/ β ratio and fractionation Acute responding normal tissue and most tumours have an α/ β of around 10Gy Late responding normal tissue have α/ β of about 3Gy. The relationship between total dose and dose per fraction relies on the α/ β ratio, Changes in the size of the dose per fraction impacts on isoeffect when the α/ β is smaller and overall treatment time is a significant factor when the α/ β is larger. So when trying to improve the tolerance of late responding normal tissue like the spine, reduce the dose per fraction! When trying to improve the isoeffect for the tumour, shorten the overall treatment time! Taken from: https://www.mdapp.co/biologically-effective-dose- bed-calculator-493/ Fractionation schedules in clinical radiotherapy Conventional / standard fractionation: o 1.8 – 2Gy, 5 fractions per week Hyperfractionation: o Dose per fraction of less than 1.8Gy o Number of fractions is increased and 2 fractions are given daily. o Allows for dose escalation when late responding normal tissue is in the field o Debateable therapeutic gain in clinical trials  Fractionation schedules in clinical radiotherapy Hypofractionation: o Dose per fraction of more than 2Gy o Number of fractions is reduced o Overall treatment time is reduced o When the α/ β ratio is smaller than the late responding normal tissue, clinical gain can be found. E.g : prostate cancers o Also used in palliative settings when late normal tissue damage is only a minor concern due to life expectancy and low total doses are used. Accelerated radiotherapy: o Reduced overall treatment time , increase in dose above 10Gy per week. o Early normal tissue reactions are expected to increase, Biologically Effective Dose (BED) Helps to understand tumour and normal tissue control when using different dose fractionation schedules. BED reports an effective dose while EQD2 reports the equivalent dose in 2Gy fractions needed to achieve the dose. Several Biologically online calculators Effective are Doseavailable. (BED) Calc ulator (mdapp.co) EQD2.com - an online EQD2 and BED calculator Fractionation and tolerance dose Tolerance tables are generally prepared for standard fractionation schedules. If we modify the fractionation, we need to calculate the equivalent dose in 2Gy fractions to understand the isoeffect. E.g: A patient with bone mets in T5 is prescribed a course of palliative radiotherapy. The prescription is 4Gy x 5 fractions to a total dose of 20Gy. Is this within spinal cord tolerance? To answer this question we need to know what the tolerance of the spine is, then we can https://en.wikibooks.org/wiki/Radiation_Oncology/ calculate the isoeffect dose in 2Gy fractions. Toxicity/QUANTEC The solution EQD2 D = Total dose d= dose per fraction α/ β = myelopathy is about 2Gy Taken from: https://www.mdapp.co/biologically-effective- dose-bed-calculator-493/ The solution EQD2 EQD2 = 30 Gy Therefore: 4Gy x 5 fractions to a total dose of 20Gy is as biologically equivalent, when considering spinal myelopathy, as 30Gy given in 2Gy fractions! Considering spinal myelopathy occurs at about 50Gy, this prescription is safe to use. More calculations… Calculations can be done by the radiobiologist to calculate what needs to be done for changes such as : o Unplanned gaps in treatment o Errors in dose delivery (e.g incorrect fraction size or number of fractions) o Changes in type of radiation delivered o Changes in dose rate o Changes in overall treatment time Caution These calculations are to be used with caution! The choice of the α/ β has a HUGE impact on the calculation! Self directed reading Find about about the FAST and CHHiP trials. What options are available to us in radiotherapy if a patient misses a treatment?