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International Atomic Energy Agency
International Atomic Energy Agency
Clinical radiobiology and Tolerance doses for large dose
Hypofractionated radiation therapy
Prof. Jolyon Hendry Clinical Radiobiologist, Christie Hospital Medical Physics and
Engineering, Manchester UK.
Chapter 5: “In hindsight”
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“Perthes (1904) in Germany recommended treatment in one session or at most a few fractions. This method, called the expedited (~4 fractions) or massive–dose (single) treatment, led to toxic reactions of unexpected severity. There followed a growing awareness of the time factor – the influence of the time during which a dose was delivered on its biological effect. The first clinical demonstration of the diminished effect of a fractionated dose was published by Krönig & Friedrich (1918). Subsequently, a battle raged for twenty-odd years between the partisans of fractionated doses and those of full (single)-dose treatments.” Summarised in Thames HD: Acta Oncol. 1988;27(2):89-103
Howard Thames
1987
HYPO HYPER
“The introduc.on of LQ into clinical prac.ce in the 1980s revolu.onised thinking and diversity in radiotherapy”
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Non-standard fractionation… Hypofractionation: Dose per fraction > 2 Gy
Fewer fractions
Hyperfractionation: Dose/fraction < 1.8-2 Gy
More fractions
Longer treatment time
Accelerated: More fractions/week
Reduced treatment time
Especially good for tumours with α/β less than for Late reactions
Good for most tumours
Good for faster-growing tumours
All schemes are aimed at improving Therapeutic Index in specific cases
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Altered dose frac.ona.on schedules
Bernier and Bentzen 2003 3/14/2013 J Hendry Hypo SRS 5
The “Rs” of Radiotherapy
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1. Repair 2. Redistribution 3. Repopulation 4. Reoxygenation
5. Radiosensitivity
6. Radiated Volume
Rodney Withers 1974
Gordon Steel 2002
Wolfgang Dörr & Bert Van der Kogel 2009
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Fractionated doses
J Hendry Hypo SRS
Hall & Giaccia 2006: Radiobiology for the Radiologist.
Early reactions (and tumours)
Late reactions
High α/β Low α/β
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Iso-Effectiveness (LQ model)
E = n1 (αd1 + βd12) = n2(αd2 + βd2
2)
D1 α + d1 = D2 α + d2 β β
BED = D 1 + d = D x R.E. (Relative Effectiveness) α /β
e.g. EQD210
E=effect n=number of fractions D=dose per fraction α/β=fractionation
sensitivity
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Alpha/Beta Ratios for Early and Late Endpoints in Different Tissues
Fowler 2005 3/14/2013 J Hendry Hypo SRS 10
α/β ratios for Human Tumors
Fowler 2005 3/14/2013 J Hendry Hypo SRS 11
DOSE-FRACTIONATION SENSITIVITY OF PROSTATE CANCER DEDUCED FROM RADIOTHERAPY OUTCOME OF 5969 PATIENTS IN SEVEN
INTERNATIONAL INSTITUTIONAL DATASETS: α/β = 1.4 (0.9-2.2) Gy
R Miralbell, SA Roberts, E Zubizarreta, JH Hendry (Int. J. Rad. Onc. Biol. Phys. 82, e17-‐24, 2012)
0.2
.4.6
.81
5 Y
ear b
RFS
60 70 80 90EQD2 (2Gy Fx)
Low risk
0.2
.4.6
.81
60 70 80 90EQD2 (2Gy Fx)
Intermediate risk
0.2
.4.6
.81
60 70 80 90EQD2 (2Gy Fx)
High risk
Androgen depriva.on
J Hendry Hypo SRS 12
Prostate External beam + HDR Brachy (3,252 patients)
3/14/2013 J Hendry Hypo SRS 13
60 80 100 120 140 160 180
5060
7080
9010
0
EQD2
5 ye
ar b
NE
D
• EBRT, open points, dashed lines
• EBRT + HDR BT, filled points + 95%CI
• Low risk, green; Inter, purple; High, red
• Circles, ASTRO; squares, Phoenix
• α/β = 1.42 Gy from EBRT analysis
• Black line, visual regression trend
• Points at far right are for HDR BT only! – 9 x 6 Gy
Tolerance doses (~1% incidence) – “large” fields Site Organ/tissue Latency EQD2 (Gy)
Digestive system: Salivary glands 1 week <20
Esophagus 3-8 months 55
Stomach 2 years 50
Small intestine 1.5 years 45
Colon 2 years 50
Rectum 1 year 60
Liver 2 weeks <30
Skin: Skin burns (large areas) 2-3 weeks 35
Late atrophy/telang. (large areas) 1 year 40
Urinary tract: Kidney 1 year 18
Bladder 6 months 55
Ureters 6 months 55-60
Nervous system: Spinal cord >6 months 55
Brain necrosis >1 year 55-60
14
QUANTEC report, IJROBP 76, Supplement, 2010; ICRP report 118, 2012 3/14/2013 J Hendry Hypo SRS
28 overexposed patients in Panama
15
Early rectal reactions 75 90 110 125 150 EQD2 Gy
Borras et al. Int. J. Rad. Oncol. Biol. Phys. 59, 539 (2004)
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Radiosurgery
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• Small volumes allow high doses to be tolerated; and delivered in a few high-dose fractions
• LQ model underestimates normal tissue tolerance at high dose per fraction?
• Hypoxia in tumours causes resistance to short-course few fractions?
Tolerance doses
3/14/2013 J Hendry Hypo SRS 17 Gay et al 2009 Rad Onc 91, 369
Human fractionation parameters – Cyberknife sites
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Tumor Normal tissue OAR Site α/β ratio (Gy) T1/2 (2)
hours Head & neck 10 4 5 Prostate 1.5 4 R - Brain ? ? >4 Lung ? 3 ? Spinal cord ? 2 >5 Pancreas, Liver, Kidney
? ? ?
In: Basic Clinical Radiobiology. Eds: Joiner & van der Kogel, 2009
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Sci. Transl. Med. 2010
All data fitted ≤3.25 Gy data fitted
Mouse lung pneumonitis: fractions every 3 hours
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20
Thames 1984: assumed T1/2=1.5 hours, LQ + incomplete repair
Wang 2010: took T1/2=0.4 hours, gLQ model
Thames re-analysis in 1993 gave T1/2 (1) = 0.40 h (0.28, 0.53) and T1/2 (2) = 4.01 h (1.55, 6.57 CI). 80% of repair is fast.
Conclusion
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If you want to project to high fractional doses: options: • Use an “incomplete repair” version (Thames) • Use a higher α/β value so that curvature is less • Modify the basic LQ model (Wang, Joiner etc) • More complex, use a “biphasic repair” version for every
sub-fraction in the schedule (Millar)
J Hendry Hypo SRS
Repair kinetics of DNA strand breaks in CHO
cells
22 3/14/2013
J Hendry Hypo SRS
Biphasic repair
Dale & Fowler 2007 23 3/14/2013
J Hendry Hypo SRS
Biphasic repair: animal systems System T1/2 (1) hours T1/2 (2) hours Author
Pig skin reactions
0.4 1.2 Van den Aardweg
Pig skin reactions
0.2 6.6 Millar et al
Mouse lung 0.4 4.0 Van Rongen
Rat spinal cord 0.7 3.8 Ang et al
Mouse kidney cells
0.2 5.0 Millar et al
Basic Clinical Radiobiology book, 2009
24 3/14/2013
J Hendry Hypo SRS
Biphasic repair: human systems System T1/2 (1) hours T1/2 (2) hours Author
Skin erythema 0.35 1.2 Turesson & Thames
Skin telangiectasia
0.4 3.5 Turesson & Thames
Skin telangiectasia
- 3.8 (2.5, 4.6) Bentzen et al
Subcutaneous fibrosis
- 4.4 (3.8, 4.9) Bentzen et al
Myelopathy - >5
Dische & Saunders
Temporal lobe necrosis
- >4 Lee et al
Basic Clinical Radiobiology book, 2009 25 3/14/2013
26 Fowler JF. Brit. J. Radiol. 83 554 (2010)
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Loss of BED vs fraction duration – for various fraction sizes (late reactions)
Half-time 0.4h+4 h Half-time 0.2h+4 h
Fowler et al, IJROBP, 59, 242, 2004
Loss of BED vs fraction duration – for various fraction sizes (tumours/early)
Fowler et al, IJROBP, 59, 242, 2004
10
When is a single dose (fraction) not a single dose?
– when it is given as multiple variable doses delivered at different dose-rates with multiple variable incomplete repair intervals, as for example by Cyber Knife
or Gamma Knife radiosurgery.
How do we deal with this from a radiobiological perspective?
Modified words of John Hopewell (Oxford) and Bill Millar (Glasgow) 2012
Single dose fraction of 13 Gy
Courtesy J Hopewell & W Millar 2013
Equivalent doses can be calculated using biologically effective dose (BED) equations
⎡ ⎤⎢ ⎥⎣ ⎦
∑n
21 2T i
i=1
φ(Ξ,µ )+cφ(Ξ,µ )1BED = D + dα/β c1+
⎡ ⎤⎢ ⎥⎣ ⎦
21 2T T
φ(Ξ,µ )+cφ(Ξ,µ )1BED = D + Dα/β c1+
Thus for true single dose exposure the BED is given by the equation:-
For a single treatment session with multiple dose fractions involving incomplete repair the BED is given by the equation:-
Courtesy J Hopewell & W Millar 2013
Variation in treatment times/protocols for 26 patients with Vestibular Schwannomas using prescription doses of either 10, 12, 13 or 14 Gy Gamma-Knife B-Series (Overall treatment time -mins)
20-30 30-40 40-50 50-60 60-70 70-80 80-90 > 90
14 Gy
3 iso-centres (2 gaps*) 25.40 - 5 iso-centres (4 gaps) - 41.28 - 6 iso-centres (5 gaps) - 40.85 - 67.78 - 13 iso-centres (12 gaps) -
129.58
13 Gy
3 iso-centres (2 gaps) - 54.55 - 6 iso-centres (5 gaps) - 61.58 74.91 - 7 iso-centres (6 gaps) - 74.89 84.61
91.96 75.36 -
92.30 8 iso-centres (7 gaps) - 124.25 12 Gy 2 iso-centres (1 gap) 29.62 - 4 iso-centres (3 gaps) - 32.65 - 39.97 5 iso-centres (4 gaps) - 50.47 - 6 iso-centres (5 gaps) - 63.07 73.97 - 7 iso-centres (6 gaps) - 80.38
8 iso-centres (7 gaps) - 63.43 - 10 Gy 5 iso-centres (4 gaps) 38.16 - 6 iso-centres (5 gaps) 49.79
7 iso-centres (6 gaps) - 57.21 8 iso-centres (7 gaps) - 73.93 -
* Gap standardised to 6 min Courtesy J Hopewell & W Millar 2013
Three voxels: Same physical prescription dose, different BED values due to protocol variations
Point 1
Point 2
Point 3
Protocol
Coll- 50% beam dose-rate imator iso-dose time (Gy/min) (mm) (Gy) (min)
1 14 6.45 5.2 2.47
2 4 3.20 2.9 2.22
3 14 6.45 5.2 2.47
Courtesy J Hopewell & W Millar 2013
Maximum variation in BED values for individual voxels in a single patient treated with 3 iso-centres, for total iso-surface doses, of 14 Gy (prescription dose in 25.4 min)
Iso-centre contribution
(Gy)
Relative contribution
(%)
Dose rate (Gy/min)
BED
Point 1 (max BED)
12.36 (shot 1) 0.17 (shot 2) 1.47 (shot 3)
88.3 1.20 10.5
2.36 0.06 0.28
85.28 (+10.0%)
Point 2 (median BED)
9.55 (shot 1) 4.09 (shot 2) 0.36 (shot 3)
68.2 29.2 2.60
1.82 0.78 0.13
80.83 (+4.2%)
Point 3 (min BED)
6.98 (shot 1) 5.05 (shot 2) 1.97 (shot 3)
49.9 36.0 14.1
1.33 0.96 0.97
77.56 (Reference)
Courtesy J Hopewell & W Millar 2013
Conclusions
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• There is enough evidence to believe that biphasic repair applies to humans
• The shorter T1/2 produces a bigger influence on fraction protraction effects (more sparing)
• With few high-dose fractions (SRS), more sparing of normal tissue than tumor if α/βtumor > α/βnormaltissue, and fraction protraction increases that, but the reverse is likely also true in some cases! e.g. prostate versus rectum.
Carbon ion hypofractionation
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• Non-small cell lung cancer • 18 fractions/ 6 weeks 9F/ 3 weeks 4F/4 days
1F/1d • 4F = 4 fields @15 GyE
1 field per day total 60 GyE
• 1F = up to 44 GyE >600 patients reported in 2012
Chiba, Japan Okada, J Rad Res 51, 355, 2010; Kamada, Int J Clin Oncol 17, 85, 2012
More details
3/14/2013 J Hendry Hypo SRS 37
Radiobiological principles: their application to γ-knife therapy. Hopewell JW, Millar WT, Lindquist C. Prog Neurol Surg. 2012;25:39-54 On the biologically effective dose (BED) - using convolution for calculating the effects of repair: I. Analytical considerations. Gustafsson J, Nilsson P, Gleisner KS. Phys Med Biol. 2013 Mar 7;58(5):1507 On the biologically effective dose (BED) - using convolution for calculating the effects of repair: II. Numerical considerations. Gustafsson J, Nilsson P, Gleisner KS. Phys Med Biol. 2013 Mar 7;58(5):1529 “Radiobiological Modelling in Radiation Oncology” Editors: Dale RE & Jones B. British Institute of Radiology (2007) “Basic Clinical Radiobiology” Editors: A.J van der Kogel and M.C. Joiner. 4th edition, Hodder Arnold (2009).