Radiation Protection in Radiotherapy

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

2. 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

3. 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

4. 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

5. 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 tumor Part 3, lecture 2: High doses in radiation therapy

6. 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), …) Part 3, lecture 2: High doses in radiation therapy

7. Survival curves Part 3, lecture 2: High doses in radiation therapy

8. 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 Part 3, lecture 2: High doses in radiation therapy

9. 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 Part 3, lecture 2: High doses in radiation therapy

10. 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 Part 3, lecture 2: High doses in radiation therapy

11. 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 Part 3, lecture 2: High doses in radiation therapy

12. 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

13. Serial organs (e.g. spine) Parallel organs (e.g. lung) Different tissue types Part 3, lecture 2: High doses in radiation therapy

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

15. 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

16. 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 Classification of radiation effects in normal tissues Part 3, lecture 2: High doses in radiation therapy

17. Early or acute reactions Late reactions Classification of radiation effects in normal tissues Late effects can be a result of severe early reactions: consequential radiation injury Part 3, lecture 2: High doses in radiation therapy

18. Late effects • Often termed complications (compare ICRP report 86) • Can occur many years after treatment • Can be graded - lower grades more frequent Part 3, lecture 2: High doses in radiation therapy

19. 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

20. 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... Part 3, lecture 2: High doses in radiation therapy

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. 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. Part 3, lecture 2: High doses in radiation therapy

23. 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) Part 3, lecture 2: High doses in radiation therapy

24. 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 Part 3, lecture 2: High doses in radiation therapy

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

26. 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 Part 3, lecture 2: High doses in radiation therapy

27. The linear quadratic model Part 3, lecture 2: High doses in radiation therapy

28. The linear quadratic model Alpha determines initial slope Beta determines curvature Part 3, lecture 2: High doses in radiation therapy

29. 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 Rule of thumb for a/b ratios Part 3, lecture 2: High doses in radiation therapy

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

31. 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 Part 3, lecture 2: High doses in radiation therapy

32. 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. Part 3, lecture 2: High doses in radiation therapy

33. 3. The 4 Rs of radiotherapy • R Withers (1975) • Reoxygenation • Redistribution • Repair • Repopulation (or Regeneration) Part 3, lecture 2: High doses in radiation therapy

34. 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 Part 3, lecture 2: High doses in radiation therapy

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. Reoxygenation Redistribution Repair Repopulation (or Regeneration) Need minimum T Need minimum t Need minimum t for normal tissues Need to reduce T for tumour The 4 Rs of radiotherapy: Influence on time between fractions, t, and overall treatment time, T Part 3, lecture 2: High doses in radiation therapy

43. Reoxygenation Redistribution Repair Repopulation (or Regeneration) Need minimum T Need minimum t Need minimum t for normal tissues Need to reduce T for tumor The 4 Rs of radiotherapy: Influence on time between fractions, t, and overall treatment time, T Cannot achieve all at once - Optimization of schedule for individual circumstances Part 3, lecture 2: High doses in radiation therapy

44. 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 Part 3, lecture 2: High doses in radiation therapy

45. 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 Part 3, lecture 2: High doses in radiation therapy

46. 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

47. 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 Part 3, lecture 2: High doses in radiation therapy

48. Evidence for “kick off” time Part 3, lecture 2: High doses in radiation therapy

49. 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

50. 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