Fractionation in Radiotherapy

1. 1

2. Fractionation in Radiotherapy By: A. Haghbin 2

3. Radiation fractionation  as cancer treatment. Fractionation  also refers to a method of treating cancer with  radiation therapy . When the total dose of radiation  is divided into several, smaller doses over a period of several days, there are fewer toxic effects on healthy cells. “FRACTIONATED” Radiation Therapy 3

4. Historical Review Earlier some radiotherapists believed that fractionated treatment was inferior & single dose was necessary to cure cancer. While radiobiological experiments conducted in France favored fractionated regimen for radiotherapy which allows cancerocidal dose to be delivered without exceeding normal tissue tolerance. 4

5. Radiobiological rationale for Fractionation The five (historically four) R's of radiobiology are concepts that explain the rationale behind fractionation of radiotherapy. The 5 R's Of Fractionation: - Repair - Redistribution - Reoxygenation - Repopulation - Radiosensitivity 5

6.    5th R and LQ model – conventional RT Linear-Quadratic Model assumes that there are two components to cell killing by radiation one that is proportional to dose (Linear) one that is proportional to the square of the dose (Quadratic) 6

7. Linear-Quadratic Model The ‘bendiness’ is determined by α/β ratio SF = e -(αD+βD2) S is the fraction of cells surviving a dose  (D ) α and β are constants. D is the dose in Gy If at a dose D, αD = βD 2 then: D = α/β 7

8. 5th R and LQ model – conventional RT The LQ model is simple and convenient – better fit in the low dose–high survival region – α (lethal/non-repairable) & β (sub-lethal/reparable) – α/β ratio for early and late reactions in human normal tissues consistent with results from experimental models 8

9. Repair Repair is the one of the primary reasons to fractionate radiotherapy. As discussed in  DNA Damage and Repair There are three types of damage that ionising radiation can cause to cells : - Lethal Damage :which is irreversible and irreparable and leads irrevocably to cell death - Potentially Lethal Damage(PLD) :The component of radiation damage that can be modified by postirradiation environmental conditions - Sublethal Damage(SLD): which under normal circumstances can be repaired in hours unless additional sublethal damage is added 9

10. Repair of Sublethal Damage Dose rate effect Type radiation Cell in different cell cycle phase Type cell 10

11. Dose-rate effect If a radiation dose is delivered in a series of equal fractions , separated by sufficient time for repair of sublethal damage to occur between doses, the effective dose-survival curve becomes an exponential function of dose . EFFECTIVE SURVIVAL CURVE FOR A MULTIFRACTION REGIMEN 11

12. Type radiation 12

13. 13

14. Cell in different cell cycle phase 14

15. Type cell Cell survival is a function of cell type and radiation type Non- or slowly proliferating cells (nerve, muscle, secretory) are less susceptible to radiation damage. Highly-proliferating cells (epithelial, stem cells) are more susceptible. 15

16. Repair and Low Dose Rate treatment If the dose rate is sufficiently low, repair may be able to take place  during  radiotherapy treatment. This considerably reduces the cell death due to sublethal damage and is one reason low dose treatments show reduced effectiveness at identical doses to high dose rate treatment . 16

17. Repair Half Life Intefraction interval and the repair half life is an important consideration when fractionating radiotherapy. Some tissues, notably the spinal cord, appear to have a slow repair mechanism with a half life of about 4 hours. It is important to separate dose by at least 6 hours and preferably 8 hours if two fractions are given on the same day. 17

18. Redistribution Cells move to more radiosensitive phase in the cell cycle between fractions. M and G2 most sensitive phases. Late S most resistant phase 18

19. Redistribution Redistribution of proliferating cell populations throughout the cell cycle increases cell kill in fractionated treatment relative to a single session treatment. Cells are most sensitive during M & G 2 phase & are resistant during S phase of cell cycle . Redistribution can be a benefit in fractionated course of RT if cells are caught in sensitive phase after each fraction 19

20. Reoygenation Cells at the center of tumor are hypoxic & are resistant to low LET radiation. Hypoxic cells get reoxygenated occurs during a fractionated course of treatment, making them more radiosensitive to subsequent doses of radiation . Tumours may be acutely or chronically hypoxic. This oxygenation status may change during treatment. 20

21. Reoygenation In this particular tumor, the process of reoxygenation is very rapid indeed . 21

22. Conventional RT and R eoxygenation 22

23. Repopulation Tends to increase cell survival. Occurs when fraction interval length greater than cell cycle doubling time . 23

24. Summery of Dose Rate Effect 24

25. Radiosensitivity Radiosensitivity is a newer member of the R's It reminds us, that apart from repair pathways, redistribution of cells, reoxygenation of malignant cells and repopulation there is an intrinsic radiosensitivity or radioresistance in different cell types. Radio sensitivity expresses the response of the tumor to irradiation. Malignant cells have greater reproductive capacity hence are more radiosensitive. 25

26. Factors affecting the radiosensitivity Physical LET (linear energy transfer):  RS Dose rate:  RS Chemical Increase RS: OXYGEN, cytotoxic drugs. Decrease RS: SULFHYDRL compounds (cys, cysteamine…) Biological Cycle status:  RS: G2, M  RS: S 26

27. 27

28. Radiation Response Response of all normal tissues to rad n is not same Depending on their response tissues are either Early responding – constitute fast proliferating cells such as skin, mucosa, intestinal epithelium, colon, testis etc. Late responding – have large no. of cells in the resting phase e.g. spinal cord, bladder, lung, kidneys etc. 28

29. Various Fractionation Schedule Fractionated radiation exploits difference in 4R’s between tumors and normal tissue thereby improving therapeutic index Types Conventional Altered Hyper fractionation Accelerated fractionation Split course Hypofractionation 29

30. Conventional fractionation Division of dose into multiple spares normal tissue through repair of SLD & repopulation of cells. Concurrently , fractionation increases tumor damage through reoxygenation & redistribution of tumor cells. Hence a balance is achieved the response of tumor & early & late reacting normal tissue. Most common fractionation for curative radiotherapy is 1.8 to 2.2Gy 30

31. Conventional fractionation Evolved as conventional regimen because it is Convenient (no weekend treatment) Efficient (treatment every weekday) Effective (high doses can be delivered without exceeding either acute or chronic normal tissue tolerance) Allows upkeep of machines. Rationale for using conventional fractionation Most tried & trusted method Both tumorocidal & tolerance doses are well documented 31

32. Hyperfractionation  the delivery of radiation in small-dose fractions( 2-3 times per day ) aims to improve the therapeutic ratio, reducing the dose given in each fraction, so as to reduce the late side effects while also permitting an increased total dose to the tumor  hyperfractionation provided the greatest benefit to patients with head and neck cancer  32

33. Hyperfractionation A hyper fractionated schedule of 80.5Gy/70(1.15Gy twice/day)/7wks compared with 70Gy/35/7wks in head & neck cancer. Implications Increased local tumor control at 5yr from 40 to59% Reflected in improved survival No increase in side effects 33

34. Accelerated Treatment Alternative to hyper fractionation Rationale – To reduce repopulation in rapidly proliferating tumors by reducing overall treatment time. Pure accelerated treatment – same total dose delivered in half the overall time by giving 2or more s/day . but it is not possible to achieve as acute effects become limiting factor. Impure accelerated treatment – dose is reduced or rest period is interposed in the middle of treatment. 34

35. Types of accelerated fraction Comparison of head & neck cases accelerated regimen 72Gy/45 ( 1.6Gy,3/day )/5wks with 70Gy/35/7wks Implications – 15% increase in loco regional control No survival adv. Increased acute effects Unexpected increase in late complications 35

36. CHART ( Continuous Hyperfractionated RT) With CHART treatments 6hrs apart delivered 3times a day,7daya a wk. with dose of 1.5Gy, total dose of 54Gy can be delivered in 36 over 12 consecutive days including weekends . Characteristics Low dose Short treatment time No gap in treatment, 3/day at 6hr interval Implications Better local tumor control Acute reactions are brisk but peak after treatment is completed Dose small hence late effects acceptable Promising clinical results achieved with considerable trauma to pt. 36

37. Split-Corse Total dose is delivered in two halves with a gap in b/w with interval of 4wks. Purpose of gap is to allow elderly pts. to recover from acute reactions of treatment further morbidity who have poorly tolerated or disease progressed despite treatment. Applied to elderly pts. in radical treatment of ca bladder & prostate & lung cancer. 37

38. Hypofractionation High dose is delivered in 2-3/ wk Rationale Treatment completed in a shorter period of time. Machine time well utilized for busy centers. Higher dose gives better control for larger tumors. Higher dose also useful for hypoxic fraction of large tumor. Disadv. Higher potential for late normal tissue complications. 38

39. 39

40. 40