Oct. 2001: 10/9 Lung—Wilmington
Clinicians View of QUANTEC
Predicting Normal Tissue Injury in the
Modern era: Knowing Our Limits
Lawrence B. Marks, M.D.
Radiation Oncology
University of North Carolina at Chapel Hill
“3D Hope”
Dose/volume
10/17/2008
Limiting Normal Tissue Risks
• Update of “Emami”
Emami”
• Emami will remain a classic
• QUANTEC: Clinically useful manner
• Data, tables, graphs
• Models
• Limitations
• Anatomy/Physiology
• DVH’
DVH’s
“3D Hope”
Dose/volume
“Reality”
Information Overload.
Which parameters?
DVH limitations
Patient/tumor factors
Normal tissue
outcome
Normal tissue
outcome
Which endpoints?
Applicability? Evolving therapies, BID, SRS, IMRT, Fx size
L. Marks/jh
1
Oct. 2001: 10/9 Lung—Wilmington
Information overload. Revenge!
No wonder we crave models, figures of metric
10/17/2008
Tables and data and lines, oh my...
• Help/Hope is on the way!
Kerry and Edwards 2004
L. Marks/jh
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Oct. 2001: 10/9 Lung—Wilmington
10/17/2008
QUANTEC
•
•
•
•
•
•
Ergo, the modelers: DVH, NTCP..
Parotid dose
Brain
Optics, ears
Parotid
Lung
Esophagus
Heart
•
•
•
•
•
•
Stomach
Kidney
Liver
Rectum
Bladder
Penile bulb
Clear progress in some areas
Liver: Univ Michigan
dry mouth
Observed and predicted NTCP, according to the LKB NTCP model vs. mean liver dose (in
1.5 Gy b.i.d.). Observed NTCP calculated from patients grouped in 4-Gy bins, with 80%
confidence intervals displayed. Predicted NTCP based on the LKB NTCP model, with n =
1.1, m = 0.18, and TD50(1) = 43.3 Gy.
Dawson et al. IJROBP 53:810-821, 2002
L. Marks/jh
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Oct. 2001: 10/9 Lung—Wilmington
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Partial Lung Irradiation
Pneumonitis after Whole Lung Irradiation
1
(3/3)
Incidence of Pneumonitis
0.9
Fit to Van Dyk data
0.8
0.6
0.5
0.4
Breur 1978
175 cGy/fx
Van Dyk 1981
Single Dose
Burgers 1998
200 cGy/fx
0.3
Rab 1976
150 cGy/fx
0.2
0.1
Salazar 1978
Single Dose
0
3
6
100
12
15
18
21
(0/40)
24
27
30
Dose (Gy)
Esophagus QUANTEC,
Yorke,
Yorke, Deasy,
Deasy, WernerWerner-Wasik
Ref 14 V=20%
Ref15 V=20%
Ref 14 corrected, V=20%
90
(1/4)
(8/56)
(0/26) (0/44)
9
Kelsey, Hubbs,
Hubbs, et. Al.
Esophagus QUANTEC, Yorke,
Yorke, Deasy,
Deasy, WernerWerner-Wasik
Newton 1969
300 cGy/fx
150 cGy/fx
0.7
1991 parameters V=20%
Ref 14 V=50%
ref 15 V=50%
80
ref 14 corrected V=50%r
70
1991 parameters V=50%
Ref 14 V=70%
Ref 15 V=70%
NTCP
60
Ref 14 corrected V=70%
1991 parameters V=70%
50
40
30
20
10
0
30
40
50
60
Dose (Gy)
L. Marks/jh
4
70
80
90
Oct. 2001: 10/9 Lung—Wilmington
100
Ref 14 Dose 50 Gy
Esophagus QUANTEC, Yorke,
Yorke,
Deasy,
Deasy, WernerWerner-Wasik
Ref 14 Dose 60 Gy
Ref 14 Dose 70 Gy
90
10/17/2008
Ref 14 Dose 80 Gy
45
Ref 11, % volume over 50 Gy
Ref 11, % volume over 70 Gy
80
3D CRT, >=Grade 2
40
IMRT, >= Grade 2
3DCRT, Grade 3
35
IMRT Grade 3
late GU toxicity (%)
70
NTCP
60
50
40
30
25
20
15
10
30
5
20
0
10
60
65
70
75
80
85
90
Prescription Dose (Gy)
0
0
20
40
60
80
100
Bladder: Yorke and Viswanathan
• Summarize data tables and figures
Discard
spatial,
anatomic,
physiologic
data
• Data is NOT great!!!
• Clinically useful, MD’
MD’s
• MD’
MD’s want it made simple
• Be careful, recognize uncertainties
• Physicists: Don’
Don’t give the MD’
MD’s false “knowledge”
knowledge”
L. Marks/jh
3D dose distribution
Extract unambiguous data
•Single Point: e.g. V20
•Global: e.g. mean dose
5
V20
Cumulative
DVH
% Volume at
QUANTEC
Dose x
% volume receiving specified dose (partial irradiation)
20 Gy
Compute modelbased NTCP
estimates
Oct. 2001: 10/9 Lung—Wilmington
DVHBased
Models
•Exportability
•Applicability
•IMRT vs.
vs. 3D
•SRS
•Model limitations
•Fractionation
•Anatomy
10/17/2008
Exportability?
Michigan (mets
(mets)) vs. Fudan/Guangxi
Fudan/Guangxi (primary liver tumors)
See letter to editor Nov 2006 from U Mich
Xu et al. IJROBP 65:193, 2006; Fudan University, Shanghai, Cancer Hospital,
Guangxi Medical University, Nanning, China
17/109 with MLD >20
70% x 17 = 12 patients
92/109 with MLD < 20
10% x 92 = 9 patients
Kong, U Mich,
Mich, IJROBP 2006
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Marks IJROBP 34:1168, 1996
Superior
Esophagus contours:
variable area (volume)
L. Marks/jh
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Inferior
Oct. 2001: 10/9 Lung—Wilmington
10/17/2008
Shower
Rat Proton Cord RT
ED 50 (Gy) to “shower”
Bath
Neighborhood Effects
No bath (control):
88 (dose in peak)
4 Gy bath, both sides
61
4 Gy bath, one side
69
18 Gy bath, both sides
31
Wide shower, 8 mm
No bath effect
Serial vs. parallel
Less well defined
Migration of stem cells
Cytokine/neighborhood effects
Vascular
Bisl et al. IJROBP 64:1204-1210, 2006
Predictors of Bleeding: Prostate Cancer Treated to 75.6 Gy
Organ interactions
Jackson IJROBP 49:685,2001
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Heart + 50% lung
50% lung
Heart + 50% lung
Proton
RT in
Rats:
Resp Rate
= f (lung
and heart
RT)
50% lung
Luijk Ca
Res 65:6509,
2005
More conservative approach
Field
Margins
Physically or
biologically
necessary margin
Too cavalier:
marginal miss
Certainty of Gross Anatomy
L. Marks/jh
What I really worry about
• Missing the tumor; Unrealistic fears
• Blocking chiasm for GBM
• Large palliative fields work!! (fast, cheep)
• Generation of fear, slaves to DVH’
DVH’s
• There was RT pre DVH’
DVH’s
• Complication = death? Usually not
• Grade 1 pneumonitis,
pneumonitis, rectal bleeding
• Don’
Don’t take data too seriously (models)
• Chemo, fraction size
Local Failure Rate : Orbital Lymphoma
Whole Orbit
Conformal
N=11 (12 eyes)
N=12
Local Recurrence
0% (0/12)
33% (4/12)
Grade 2 Toxicity
33% (4/12)
25% (3/12)
From Pfeffer et al., IJROBP 2004
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Oct. 2001: 10/9 Lung—Wilmington
Are we ready to base treatment
decisions on DVH’
DVH’s?
10/17/2008
Old fashioned ways to reduce toxicity
• Ready access to dose statistics
• Positioning
• Neck
• Decubital
• Reducing skin folds
• Barium in bowel
• Careful team work
• Keep it simple!!, use time wisely
• UserUser-defined figures of merit
Applicable in Modern Era!
• Yes! I hope so, since we are doing it
• Overtly or indirectly
• Monitor what we are doing
• Vendors need to help us
Summary
• Since Emami
• More 3D dosimetry-> toxicity data
dosimetry-->
• Liver, Parotid, lung, esophagus, brain, rectum
• DVHDVH-based predictions subsub-optimal (physiology?)
• Is the prior data still applicable?
• 3D beams -->
--> IMRT
• Beam number, fraction size
• ChemoChemo- moving target
• BID RT
• Challenges for normal tissue injury studies
• Reliance on technology to reduce morbidity
• IMRT, OBI, CBCT, etc
L. Marks/jh
Acknowledgments
• Jessica Hubbs,
Hubbs, Jinli Ma, Jiho Nam, Junan Zhang
• Physicists: Duke and UNC
• Varian Medical Systems, Lance Armstrong
Foundation, DOD, NIH
• PLUNC (University North Carolina at Chapel Hill)
• QUANTEC colleagues
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Oct. 2001: 10/9 Lung—Wilmington
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CT
3D
Beams
Apertures
Not
O.K.
Right Lung
Esophagus
Spinal Cord
TCP
NTCP
O.K.
Computer Not
Magic
O.K.
Treat
DVH
Assess doses and
beam
orientation &
aperture
Apply prior knowledge
Consider Concurrently
New York Times
Tuesday, April 11, 2006
L. Marks/jh
Dose
Constraints
Contour
Segment
DVH
Heart
Left lung
IMRT
11
O.K.
Assess
DVH’s
Beam orientations, “apertures,”
intensity maps not intuitive.