Clinical radiobiology and Tolerance doses for large dose ... · BED = D 1 + d = D x R.E. (Relative...

$: Clinical radiobiology and Tolerance doses for large dose ... · BED = D 1 + d = D x R.E. (Relative Effectiveness) α /β e.g. EQD2 10 E=effect n=number of fractions D=dose per fraction$
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”

3/14/2013 J Hendry Hypo SRS 2

“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”


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

3/14/2013 4 J Hendry Hypo SRS

Altered dose frac.ona.on schedules

Bernier and Bentzen 2003 3/14/2013 J Hendry Hypo SRS 5

The “Rs” of Radiotherapy


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

3/14/2013 7

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


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


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)


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)

3/14/2013 J Hendry Hypo SRS

Radiosurgery


•  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


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


Sci. Transl. Med. 2010

All data fitted ≤3.25 Gy data fitted

Mouse lung pneumonitis: fractions every 3 hours


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


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)


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:-


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


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)


Conclusions


•  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


•  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


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).

Clinical radiobiology and Tolerance doses for large dose ... · BED = D 1 + d = D x R.E. (Relative...

Documents

Transcript of Clinical radiobiology and Tolerance doses for large dose ... · BED = D 1 + d = D x R.E. (Relative...