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Towards 4D radiation biology
Søren M Bentzen, Ph.D., D.Sc.
Departments of Human Oncology; Medical Physics; Biostatistics and Medical Informatics,
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
bentzen@humonc.wisc.edu
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From 0D to 1D: It’s about time!
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Human tumor fractionation sensitivity Bentzen & Ritter 2005
Prostate
Owen et al. 2006
Breast
Geh et al. 2006
Esophagus
Bentzen et al. (in press)
HNSCC
Melanoma
Bentzen et al. 1989
Liposarcoma
Thames & Suit 1986
0
5
10
15
20
(Gy)
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The 4R’s and dose‐rate effects
Regaud dose-rate
REPOPULATION
REOXYGENATION
REDISTRIBUTION
REPAIR
0.01
0.1
1
10
100
1000
Dose rate (cGy/min)
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Multiple fractions per day and low dose‐rate
Lea‐Catcheside factor
2
∙
∙
2
 Limits of the Lea‐Catcheside factor, g: • n fractions per day with inter‐fraction interval t
• g→1 as t→
• g→n as t→0
• Continuous low dose‐rate irradiation delivered over time t
• g→0 as t→
• g→1 as t→0
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Multiple fractions per day and low dose‐rate
Lea‐Catcheside factor
2
∙
  t1 1 exp
exp( 
∙  t )
∙
g2∙ 2 ∙
(∙  t ) 2
log e (2) log
2

T1 2
2
MONO-EXPONENTIAL RECOVERY KINETICS
Continuous low dose‐rate irradiation delivered over time t
• g→0 as t→
• g→1 as t→0
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Two (or more?) recovery components
2
∙
∙
∙
∙
2
 The partition coefficients:
• 1+2=1
• (/)1 = (/)2 ??
 The limit of the Lea‐Catcheside factor
• n fractions per day with inter‐fraction interval t
• gi→1 as t→
• gi→n as t→0
• Continuous low dose‐rate irradiation delivered over time t
• gi→0 as t→
• gi→1 as t→0
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Recovery halftimes: animal data
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Two recovery components in spinal cord
Two parallel catheters inserted on each side of the vertebral bodies of the rat spinal column (Th10 ‐
L4)
HDR‐microSelectron. Interstitial irradiation with a stepping 192Ir‐point source, varying the activity of the point source between 0.3 and 6.5 Ci
Continuous irradiation with Ir
wires
 Pop et al. R&O 55: 301 (2000)
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Two recovery components in spinal cord
Authors’ conclusion:
two repair processes with T1/2 of 0.19 h and 2.16 h Partition coefficient of 0.98 for the
longer repair process.
 Pop et al. R&O 55: 301 (2000)
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THANKS TO
JOHN
HOPEWELL
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LQ‐model: limits of applicability
Low dose hyper-radiosensitivity (?)
0
1
2
3
4
5
6
7
8
9
10
Dose per fraction (Gy)
1
0.6 Gy/F
0.9
0.8
0.7
0.6
0.5
0
0.5
1
1.5
2
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EB accelerated partial breast irradiation  38.5 Gy in 10 F over 5 days (NSABP B‐39/RTOG 0413)
 /=3.8 Gy  EQD2=52 Gy
 Jagsi et al. IJROBP 76: 71 (2010)
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APBI with EBRT – late effects
 34 patients enrolled, study closed early after 7 patients developed unacceptable cosmesis
 Authors’ conclusion: “The hypofractionated
schedule…may be suboptimal”
 Jagsi et al. IJROBP 76: 71 (2010)
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NSABP B‐39 schedule: incomplete recovery
80
38.5 Gy in 10 F
b.i.d. – 6-hour interval
75
70
EQD2 (Gy)
65
60
Fibrosis – Bentzen 1999
55
Telangiectasia – Bentzen 1999
50
45
40
0
1
2
3
4
Recovery half‐time (hours) 5
 Bentzen & Yarnold IJROBP 77: 969 (2010)
6
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Human recovery halftimes
Endpoint
Delivery
Erythema, skin
MFD
0.35 OR 1.2
T1/2 (h)
95% CL Source
?
Mucositis, H&N
MFD
2–4
?
Bentzen et al. (1996)
Mucositis, H&N
FLDR
0.3‐0.7
?
Denham et al. (1995)
Turesson/Thames (1989)
Laryngeal oedema
MFD
4.9
Rad myelopathy
MFD
> 5
?
Dische/Saunders (1989)
Skin telangiectasia
MFD
0.4 OR 3.5
?
Turesson/Thames (1989)
[3.2; 6.4] Bentzen et al. (1999)
Telangiectasia
MFD
3.8
[2.5; 4.6] Bentzen et al. (1999)
Subcut. Fibrosis
MFD
4.4
[3.8; 4.9] Bentzen et al. (1999)
Temp lobe necrosis
MFD
Various pelvic compl HDR/LDR
> 4
?
Lee et al. (1999)
1.5‐2.5
?
Fowler (1997)
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From 1D to 4D: The space odyssey
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The dose‐volume trade‐off
Geographical miss
Dose‐dependent failure
DOSE
HOW MUCH?
VOLUME
WHERE?
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QUANTEC
 Proposed by AAPM Science Council (Mackie & Yorke)  Steering committee consists of physicists, modelers, and physicians (Bentzen, Constine, Deasy, Eisbruch, Jackson, Marks, Ten Haken, Yorke). Weekly conference calls Feb. ’07–Mar. ‘10.
 Jointly supported by AAPM and ASTRO
 Madison kick‐off meeting, Oct. 2007: ~60 attendees
 ASTRO‐funded IJROBP supplement (March 2010): • 3 introductory papers,
• 16 site‐specific review papers, • 5 ‘Vision’ papers outlining future research directions
 QUANTEC issue, IJROBP 76(3), suppl. 1: pp. 1–160 (2010)
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What’s (largely) missing from QUANTEC?
 Effect of non‐dosimetric risk factors
 Interaction between dose distribution and fractionation
 Influence of cytotoxic and molecular targeted agents on dose distribution effects
 Bentzen et al. IJROBP 76: S3 (2010)
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Not all voxels are created equal
48 patients treated for localized prostate cancer
Endpoints: fecal incontinence, frequency, urgency
I: internal anal sphincter; E: external anal sphincter; P: puborectalis muscle; L: levator ani muscles
 Smeenk et al. IJROBP (in press)
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Irradiating multiple organs
Single fraction irradiation of Wistar rats
150 MeV protons – shoot‐
through technique
Very uniform dose distribution in the longitudinal direction ( 1%)
Sharp lateral field edges (20–
80% isodose distance: 1 mm)
 Van Luijk et al. IJROBP 69: 552 (2007)
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Risk factors for radiation pneumonitis
 Significant risk factors for RP: •
•
•
•
•
•
Older age Disease located in mid‐lower lung Presence of comorbidity Ongoing smoking was found to protect against RP History of smoking tended to protect against RP Sequential (v. concomitant) chemotherapy scheduling (OR=1.7, p<0.0001), (OR=1.9, p=0.002), (OR=2.3, p=0.007). (OR=0.6, p=0.008). (OR=0.7, p=0.06). (OR=1.6, p=0.01)
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Hypofractionation – effect of dose distribution
90
70
60
%
50
40
30
20
10
0
100
80
60
40
20
% isodose contour
0
EQD2 – Late effects (Gy)
80
Standard fractionation:
70 Gy in 35 F
For a tumor with /=6 Gy
this is equivalent to 56 Gy in 14 F (@ the 100% isodose)
‐ NO TIME FACTOR ASSUMED
For a late side‐effect with
/=3 Gy the EQD2 at the 100% isodose is 78.4 Gy However, the EQD2 at lower isodoses will be LESS for the HFX plan than the conventional plan
 Nahum & Bentzen R&O 73 (Supp. 1): S174 (2004)
 Jin et al. IJROBP 76: 782 (2010)
 Vogelius et al. Acta Oncol 49: 1052 (2010)
 Mizuta et al. IJROBP (in press)
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Dose distribution and chemoradiation
3D-CRT
TOMOTHERAPY
IM PROTON THERAPY

18 pts w. non‐small cell lung cancer treated with helical tomotherapy

3 alternative plans optimized without taking chemo into account

Chemotherapy modeled as a uniform chemotherapy equivalent radiation dose 
Endpoint: grade 2 RP 
NTCP model: the critical volume model.
 Vogelius et al. IJROBP 80: 893 (2011)
 Vogelius et al. Acta Oncol 50: 772 (2011)
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Dose per fraction escalation in NSCLC
 18 pts. with NSCLC
• Treated with helical tomotherapy
• Re‐planned with 3D‐CRT
Vogelius et al. Acta Oncol 49: 1052 (2010)
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Optimal dose distribution  chemo
 Vogelius et al. IJROBP 80: 893 (2011)
 Vogelius et al. Acta Oncol 50: 772 (2011)
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Increased Oral Mucositis after IMRT versus Non‐IMRT when Combined with Cetuximab and Cisplatin or Docetaxel for Head and Neck Cancer: Preliminary Results of RTOG 0234
D Khuntia, J Harris, SM Bentzen, MS Kies, JN Myers, RL Foote, M Machtay, MZ Rotman, WL Straube, KK Ang, PM Harari
1University of Wisconsin; 2RTOG Headquarters; 3University of Texas MD Anderson Cancer Center; 4Mayo Clinic; 5Thomas Jefferson University; 6SUNY Downstate Medical Center; 7Washington University St. Louis
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RTOG 0234 – Treatment Schema
Week 1
Cetuximab
400 mg/m2 day 1
Weeks 2- 7
RT plus weekly Cetuximab and N = 119
Cisplatin RT (60 Gy (2 Gy/day)/6weeks)
Cetuximab (250 mg/m2/wk)
Cisplatin (30 mg/m2/wk)
R
Stratification: Cetuximab
• PS 0 – 1
• Risk Category
400 mg/m2 day 1
‐ Positive margins
‐ High Risk (> 2+ nodes or extranodal spread)
RT plus weekly Cetuximab and Docetaxel
N = 119
RT (60 Gy (2 Gy/day)/6weeks)
Cetuximab (250 mg/m2/wk)
Docetaxel (15 mg/m2/wk)
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RTOG 0234 – Results
 Univariate analysis
• Higher mucositis in IMRT vs non‐IMRT patients (45% vs
26%, p=0.006) • No difference in Grade 3/4 mucositis between CDDP and docetaxel (36% vs 31%, p=0.56)
 Multivariate analysis • IMRT (p=0.001) and oral cavity as primary site (p=0.014) significant
• Cytotoxic agent (p=0.85) not significant
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The ICRU Bioeffect Modeling Committee
 International Commission on Radiation Units and Measurements
 Report Committee #25: “Bioeffect Modeling and Equieffective Dose Concepts in Radiation Therapy”
 Chairs: Bentzen & Wambersie
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Human recovery halftimes estimated from multiplefractions per day schedules are in the order of
0%
0%
0%
0%
0%
1.
2.
3.
4.
5.
1-2 minutes
10-15 minutes
1-1.5 hours
3-5 hours
1-2 days
10
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In the LQ model the kinetics of recovery between fractions
or during continuous irradiation is represented by
0%
0%
0%
0%
0%
1.
2.
3.
4.
5.
The α/β ratio
The Lea-Catcheside g-factor
The magnitude of β
The Heaviside function
The overall treatment time
10
Modeling studies suggest that dose plans delivering ‘a
small dose to a large volume’ of normal tissue will make…
0%
0%
0%
0%
0%
1.
2.
3.
4.
5.
hypofractionation more attractive
chemoradiation more attractive
hypofractionation more toxic
accelerated fractionation less toxic
hyperfractionation more attractive
10
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