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# TIME DOSE & FRACTIONATION

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Introduction
Time dose & fractionation
Therapeutic index
Survival Curves Of Early & Late Responding Cells
Various fractionation schedules
Clinical trials of altered fractionation

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### TIME DOSE & FRACTIONATION

1. 1. CONTENT PART A • Introduction • Time dose & fractionation • Therapeutic index • Four R’s Of Radiobiology • Radiation response • Survival Curves Of Early & Late Responding Cells • Various fractionation schedules • Clinical trials of altered fractionation PART B • Physical Models For Time Dose & Fractionation • Strandqvist Plot • Cohen’s Formula • Fowler Concepts • NSD Model • TDF model • Target Theory • L Q model • BED calculation of different fractionation regimen
2. 2. AIM OF RADIOTHERAPY • To deliver precisely measured dose of radiation to a defined tumor volume with minimal damage to surrounding normal tissue. • Aims: • To eradicate tumor, • Improve quality of life & • Prolongation of survival.
3. 3. Time • Time factor is overall time to deliver prescribed dose from beginning of course of radiation until its completion. • Effect of treatment varies enormously with time. Hence dose should always be stated in relation to time • General rule is longer the overall duration of treatment greater is the dose required to produce a particular effect. • Local control is lost when treatment time is prolonged and early toxicity increased when time is too short ,
4. 4. Time depends on • 1. Intension to treat For curative purposes overall t/t is 5-6wks  Better tumor control with minimal morbidity  Tumor response can be monitored.  Radiation reactions can be monitored.  If treatment time is more than 6wks then dose has to be increased Short duration treatment time is justified for  Treatment of small lesions: SRS/SRT  To treat aged persons  Palliative treatments • 2. Site of tumor  Rapidly proliferating tumor has poor LC with increase in time eg- head & neck, NSCLC  In slowly growing tumor eg. Breast and prostate overall treatment time not
5. 5. CLINICAL IMPLICATION OF OTT • Overall treatment time is a very important factor for fast-growing tumors. • In head and neck cancer, local tumor control is decreased by about 1.4% (range of 0.4% to 2.5%) for each day that the overall treatment time is prolonged. • The corresponding figure for carcinoma of the cervix is about 0.5% (range of 0.3% to 1.1%) per day. • Such rapid proliferation is not seen in breast or prostate cancer.
6. 6. Dose • Amount of energy absorbed per unit mass of tissue Absorbed Dose • RAD- when 100 ergs of energy is deposited per gram of tissue (100ergs/gram) • ▶ SI unit is Gray:1 Gy =1joule/kg or 100 rads Equivalent dose=absorbed dose x radiation weighing factor (Sievert) Effective Dose: Equivalent dose ×tissue weighing factor (Sievert)
7. 7. TUMOR LETHAL DOSE • Dose of radiation that produces complete & permanent regression of tumor in vivo in zone irradiated. • The expression of relationship b/w lethal effect & dose was first propounded by Holthusen • Consequences of his working hypothesis are :- • There is a dose point A below which there is no appreciable lethal effect. • As dose is increased lethal effect increases • At upper end of sigmoid curve there is a point TLD at which 80-90% tumor resolves completely • Above this point dose has to be increased considerably to gain any appreciable rise in lethal effect. Probability of cell death 100% A TLD %agelethaleffect dose
8. 8. TISSUE TOLERANCE • In RT the success of eradicating tumor depends on radio sensitivity of tumor as well as tolerance of surrounding normal tissue • NTT limits the max. dose that can be delivered to tumor eg in cervix & esophagus • Usually <5% damage to normal tissue is acceptable
9. 9. NTT: Factors • Site of tissue – axilla, perineum less tolerant • Area or volume irradiated • Vascularity & Supporting tissues ( stroma and parenchymal cells) • Individual variation of tolerance.(intrinsic radiosenstivity)
10. 10. Therapeutic index • It is ratio of TLD/NTT • This ratio determines whether a particular disease can be treated or not • TLD > NTT then radical dose of radiation cannot be delivered. • The more the curve B is to the right of curve A the more is therapeutic ratio • The optimum choice of radiation dose delivery technique is one that maximizes the TCP & simultaneously minimizes the NTCP
11. 11. Therapeutic index: The more the curve B is to the right of curve A the more is therapeutic ratio
12. 12. Dose varies with 70 GY
13. 13. 3.Fractionation
14. 14. History: Introduction Of Fractionation
15. 15. Regaud’s Experiment • ▶ Tried to sterilize sheep by irradiation of their testis. • ▶ Testis were regarded as model of a growing tumor & skin as dose limiting normal tissue. • ▶ He found that- • ◦ Single dose – sterilization possible only with unacceptable skin damage • ◦ Fractionated dose – sterilization achieved without excessive damage to skin of scrotum. • ▶ Later confirmed by different such experiment in Ram between 1920 and 1930 in Paris
16. 16. FOUR R’s OF RADIOBIOLOGY
17. 17.  Figure 5.3 shows data obtained in a split dose experiment with cultured Chinese hamster cells.  A single dose of 15.58 Gy leads to a SF of 0.005.  If the dose is divided into two approximately equal fractions separated by 30 min SF is already appreciably higher than for a single dose.  As the time interval is extended, SF increases until a plateau is reached at about 2 hours, corresponding to a surviving fraction of 0.02.  The increase in survival in a split-dose experiment results from the repair of sublethal radiation damage The data were obtained with cultured mammalian cells maintained at room temperature (24° C) between the dose fractions to prevent the cells from moving through the cell cycle during this interval.
18. 18. • Radiation kills cell in the dividing phase of cell cycle • Main mode of injury : mitotic cell death • Cells are most sensitive in mitotic phase • Resistance is greatest in late S phase • If cell cycle is considerable length then another phase of resistance is obtained in early G1 phase followed by sensitive phase at G2 REDISTRIBUTION
19. 19. REDISTRIBUTION
20. 20.  Figure 5.4 shows the results of a parallel experiment in which cells were exposed to split doses and maintained at their normal growing temperature of 37° C.  The pattern of repair seen in this case differs from that observed for cells kept at room temperature.  In the first few hours, prompt repair of SLD is again evident, but at longer intervals between the two split doses, the surviving fraction of cells decreases, reaching a minimum with about a 5-hour separation.  In Chinese hamster cells, most of the survivors from a first dose of radiation are located in the S phase of the cell cycle.  If about 6 hours are allowed to elapse before a second dose of radiation is given, this cohort of cells progresses around the cell cycle and is in G2/M, a sensitive period of the cell cycle at the time of the second dose.
21. 21.  If the increase in radiosensitivity in moving from late S to the G2/M period exceeds the effect of repair of SLD, the surviving fraction falls.  The pattern of repair shown in Figure 5.4 is therefore a combination of three processes occurring simultaneously.  First, there is the prompt repair of sub lethal radiation damage.  Second, there is progression of cells through the cell cycle during the interval between the split doses:reassortment.  Third, there is an increase of surviving fraction resulting from cell division, or repopulation, if the interval between the split doses is from 10 to 12 hours, because this exceeds the length of the cell cycle of these rapidly growing cells.
22. 22. REPOPULATION • In normal tissues, homeostatic response following radiation injury, involve: • reduction of cell cycle time: rapid doubling • increase in growth fraction(e.g recruitment of resting cells) • decrease in cell loss factor • • In tumors, rate of cell production exceeds rate of cell loss. Repopulation may involve any of above three mechanisms. • ▶ Repopulation may help to spare normal tissue damage but may also reduce tumor control probability
23. 23. Accelerated Repopulation: clinical implication • Accelerated repopulation starts in head and neck cancer in humans about 4 weeks after initiation of fractionated radiotherapy. • About 0.6 Gy per day is needed to compensate for this repopulation.
24. 24. REOXYGENATION • Cells at the center of tumor are hypoxic & are resistant to low LET radiation. • A dose of x-rays kills a greater proportion of aerated cells than hypoxic cells because aerated cells are more radiosensitive. • Therefore, immediately after irradiation, most cells in the tumor are hypoxic. • Hypoxic cells get reoxygenated during a fractionated course of treatment • Possible mechanisms:  ▶ Recirculation through temporarily closed vessels after acute hypoxia  ▶ Release of chronic hypoxia due to tumor size shrinkage
25. 25. SUMMARY
26. 26. • Response of all normal tissues to radiation 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. RADIATION RESPONSE
27. 27. • This diagram shows that time after the start of fractionated regimen at which extra dose is required to compensate for cellular proliferation is quite different for late- versus early-responding tissues. • The other point made, of course, is that these are data from rodents and that in the case of humans, the time scales are likely to be very much longer • In particular, the time at which extra dose is required to compensate for proliferation in late- responding tissues in humans is far beyond the overall time of any normal radiotherapy regimen. • Prolonging overall time within the normal radiotherapy range has little sparing effect on late reactions, but a large sparing effect on early-responding tissues.
28. 28. RADIATION RESPONSE: EARLY REACTING TISSUE • Early responding tissues are triggered to proliferate within 2-3wks after start of fractionated RT. • Prolonging overall treatment time can reduce acute reactions without sparing late damage • Fraction size & overall t/t both determine response of acutely responding tissues. • Large fraction size may produce irreparable lethal damage • Prolong OTT may repair SLD in early tissues
29. 29. RADIATION RESPONSE: LATE REACTING TISSUE • Late reacting tissues are more sensitive to changes in fractionation pattern than early responding tissues.  ▶ Fraction size is dominant factor in determining late effects.  ▶ Overall t/t has little influence on late effects.  If fewer and larger dose fractions are given, late reactions are more severe, even though early reactions are matched by an appropriate adjustment in total dose.
30. 30. • Survival curves of early & late responding cells have different shapes. • Curves for late responding tissue are more curved because of difference in repair capacity of late & early responding tissues. Survival Curves Of Early & Late Responding Cells
31. 31. • For early effects, à/ ß ratio is large  as a consequence, à (irreparable damage) dominates at low doses, so that the dose- response curve has a marked initial slope and does not bend until higher doses.  The linear and quadratic components of cell killing are not equal until about 10 Gy. • For late effects, à/ ß ratio is small  so that ß (repaieable damage ) has an influence at low doses.  The dose-response curve bends at lower doses to appear more curved  the linear and quadratic components of cell killing are equal by about 3 Gy.
32. 32. EXPLANATION FOR DIFFRENCE IN SHAPE OF EARLY & LATE RESPONDING TISSUES • The radio sensitivity of a population of cells varies with the distribution of cells through the cycle . • Two different cell populations may be radio resistant :- 1. Population proliferating so fast that S phase occupies a major portion of cycle .(early responding tissue) 2. Population proliferating so slowly that many cells are in early G1 or not proliferating at all so that cells are in resting (G0) phase (late responding tissue).
33. 33. • Population proliferating so fast that S phase occupies a major portion of cycle . • Redistribution occurs through all phases of cell cycle in such population & is referred to as self sensitizing activity. • New cells produced by fast proliferating population offset cells killed by dose #s & thus offers resistance to effect of radiation in acutely responding tissues & tumors. • Thus proliferation occurring b/w dose #s help in repopulation of normal tissue (i.e. spares normal tissue) at the risk of tumor repopulation EXPLANATION FOR DIFFRENCE IN SHAPE OF EARLY RESPONDING TISSUES
34. 34. • Population proliferating so slowly that many cells are in earlyG1 or not proliferating at all so that cells are in resting (G0)phase. • Hence late responding normal tissue are resistant due to presence of many resting cells. • Such resistance disappears at high dose/# EXPLANATION FOR DIFFRENCE IN SHAPE OF LATE RESPONDING TISSUES
36. 36. Aim: to find whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma. Lancet. 2003 1485 patients treated with primary radiotherapy alone,
37. 37. Primary locoregional tumour control as function of number of fractions per week Overall 5-year locoregional control rates were 70% and 60% for the six-fraction and five- fraction groups, respectively (p=0.0005). primary tumour control (76 vs 64% for six and five fractions, p=0.0001), but was non-significant for neck- node control
38. 38. Disease specific survival Overall survival Disease-specific survival improved (73 vs 66%) for six and five fractions but not overall survival
39. 39. Early and late radiation-related morbidity Acute morbidity was significantly more frequent with six than with five fractions, but was transient. CONCLUSION Accelerated radiotherapy applied to squamous- cell carcinoma of the head and neck yields better locoregional control than does a conventional schedule with identical dose and fractionation.
40. 40. 2010 IAEA-ACC
41. 41. 1997
42. 42. RESULTS OF CHART • The results of the CHART protocol showed good local tumor control with severe acute reactions. • It was claimed that patients favoured the protocol because treatment was concluded quickly. • The incidence of late effects in general did not increase and by some measures actually decreased. • The notable exception was damage to the spinal cord. • Several myelopathies were recorded at total doses of 50 Gy, the probable cause being that an interfraction interval of 6 hours is not sufficient for the full repair of sublethal damage in this tissue.
43. 43. REASONS FOR INCREASED LATE TOXICITY IN EORTC TRIAL • This EORTC trial and several other trials testing accelerated treatment show that attempting to keep the total dose as high as 66 to 72 Gy, but shortening OTT by as much as 2 to 3 weeks from a conventional time of 6 or 7 weeks leads to serious late complications. • There are probably two reasons for this: • First, the late effects observed are “consequential” late damage, that is, late damage developing out of the very severe acute effects. • Second, there is incomplete repair between dose fractions if several fractions per day are given. • This is especially likely for protocols involving 3# per day, in which any unrepaired damage in the first interval accumulates in the second interval in each day and also because intervals between fractions of only 4 hours were used in the early years of the EORTC trial.
44. 44. . • Patients with stage III or IV SCC (n=1076) were randomized to 4 treatment arms: 2000
45. 45. (1) Standard fractionation 70 Gy/35 daily fractions/7 weeks (2) Hyper fractionation 81.6 Gy/68 twice-daily fractions/7 weeks (3) Accelerated fractionation with split 67.2Gy(1.6bid)/42 fractions/6 weeks with a 2-week rest after 38.4 Gy (4) Accelerated fractionation with concomitant boost 72 Gy/42 fractions/6 weeks.(1.8Gy/f with 1.5 Gy /f boost on last 12 fractions)
46. 46. RTOG 90-03 Results: • LRC: • significant improvement in 2 yr LRC for the hyper fractionation and concomitant boost arms . • DFS: • trend toward improved DFS (p = 0.067 and p = 0.054 respectively for the hyper fractionation and concomitant boost arms • OS: difference in overall survival was not significant. • TOXICITY: • altered fractionation regimens were associated with higher incidence of grade 3 or worse acute mucosal toxicity, but no significant difference in late toxicity
47. 47. MARCH META-ANALYSIS 2006 2010 The Lancet, Volume 368, Issue 9538, Pages 843 - 854, 2 September 2006
48. 48. 15 Randomized Trials of Varied Fractionation (1970-1998) PATIENT CHARACTERISTICS 7073 patients Tumours sites: mostly oropharynx and larynx 74% patients had stage III—IV disease hyper fractionated accelerated accelerated with total dose reduction Overall survival was the main endpoint median follow up:6 yr
49. 49. benefit Conventional vs Altered Hyper fractionation vs Accelerated fractionation Locoregional control Loco regional control 6.4 %times higher benefit was higher with hyper fractionated radiotherapy ( OS 8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1·7% with total dose reduction at 5 years, p=0·02) Survival benefit absolute benefit of 3·4% at 5 years with altered fractionated radiotherapy,
50. 50. RESULTS OF MARCH META-ANALYSIS: There was a significant survival benefit in altered fractionation.(3.4%at 5 years) There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6·4% at 5 years; p<0·0001 The benefit was significantly higher in the youngest patients Interpretation Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit
51. 51. LESSONS LEARNED FROM ALTERD FRACTIONATION STUDIES • First, hyperfractionation appears to confer an unequivocal benefit in the treatment of head and neck cancer, in terms of both local control and survival, without a significant increase in late sequelae. • By contrast, caution is needed in the application of accelerated treatment because the EORTC trials showed an unexpected increase in serious complications, both early and late. • Particular caution is necessary if the spinal cord is in the treatment field for twice-a-day treatments because repair of sublethal damage has a slow component in this tissue.
52. 52. HYPOFRACTIONATION: history • During the 1970s and the 1980s, the trend in radiotherapy, particularly in the United States, has been to HYPERFRACTIONATION to reduce the severity of late effects as described in detail previously. • However because of logistic reasons with hyperfractionation a new fractionation regimen evolved giving dose fractions much larger than 2 Gy for curative radiotherapy • Four lines of research point in this direction.
53. 53.  In the special case of prostate cancer, à/ß ratio is low, range of 2-3—more similar to late-responding normal tissues than to tumors.  This essentially removes the basic rationale for a multifraction regimen of 35 or more fractions.  The implication is that an EBRT regimen consisting of a smaller number of larger dose fractions, or alternatively high dose rate (HDR) brachytherapy delivered in a limited number of fractions, should result in good local tumor control without increased normal tissue damage First evidence
54. 54. Second evidence Second, the outcome of several large fractionation trials, mainly involving head and neck tumors, and particularly the CHART trial, have clearly demonstrated the advantage of “ acceleration,” that is, shortening the overall treatment time to improve local control. On the other hand, the demonstration that the half-times of late normal tissue repair are long severely limits the strategy of using multiple treatments per day to attain acceleration The only alternative to achieve acceleration is a smaller number of larger dose fractions.
55. 55. Third evidence  The development of IMRT ,Tomotherapy, and proton beams results in greater conformity  This means greatly improved dose distributions, with smaller volumes of normal tissues receiving high doses.  This suggest possibility of increasing the dose per fraction, because need to spare late responding normal tissues by fractionation is Reduced because of the lower dose to these tissues. 3DCRT IMPT
56. 56. The development of carbon ion beams has led to trials involving treatment with a small number of large dose fractions. It is not clear at present whether the apparent success of this strategy is caused by the superior dose distribution due to Bragg Peak, or the relatively high LET & RBE of the radiation. Fourth evidence
57. 57. HYPOFRACTIONATION: INDICATION • (a) for prostate cancer for which the à/ß ratio is closer to that for late- responding tissues, which removes the benefit of fractionation; • (b) for IMRT and proton beams, where the dose distribution is so improved that the volume of normal tissue exposed to high doses is much reduced • (c) for carbon ion beams, where the dose distribution is improved and, in addition, the radiation has a relatively high LET.
58. 58. Clinical implication • Carcinoma breast • Lung cancer
59. 59. Role of Hypofractionation in breast carcinoma Lancet Oncol 2008; 9: 331–41 START Trial A & B
60. 60. TRIAL PROFILE •START A • Criteria: Early breast cancer (pT1-3, pN0-1 M0); BCS or Mastectomy 50 Gy in 25 fractions over 5 weeks 41.6 Gy/3.2Gy per fraction in 13 fractions over 5 weeks, or 39 Gy/3Gy per fraction in 13 fractions over 5 weeks •START B Criteria: Early breast cancer (pT1-3, pN0-1 M0) 50 Gy/2 Gy per fraction, 25 fractions over 5 wks, 40 Gy/2.67 Gy per fraction,15 fractions over 3 wks.
61. 61. RESULTS OF START A & B • START A • START B • 10-year rates of local-regional relapse: 50 Gy: 5.5% 40 Gy: 4.3% (p=0.21) Results- 10-yr
62. 62. DFS in Start a & b
63. 63. Conclusion of START TRIALS • The combined trials present mounting evidence that hypofractionation is a safe and effective approach to breast cancer radiotherapy. • Utilization of hypofractionation may offer considerable savings to individual patients and the healthcare system—without compromising clinical outcomes or quality of life.
64. 64. HYPOFRACTIONATION IN LUNG CANCER- RATIONALE • Conventional XRT limited to 70Gy • Duration of therapy 6 to 7 weeks for conventional therapy is difficult for patients to complete • SBRT: Biologic Equivalent doses greater than 120Gy at 2Gy/fx Typically 5 or less treatments– high dose per treatment Highly focused radiation concentrated on the tumor with sub-millimeter accuracy Continuous tumor tracking – via respiratory gating
65. 65. SBRT IN LUNG CANCER