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Evolution of Novel Radiation Strategies to Improve Therapeutic
Index for Lung Cancer Lawrence B. Marks, M.D.
University of North Carolina at Chapel Hill, NC
UNC
Disclosures Marks Grants: Current: NIH, CDC, Elekta Recent: Lance Armstrong, Dept Defense Unpaid consultant Siemens, Elekta Dept Grants/Affiliations: Current: Siemens, Accuray/Tomotherapy, Morphormics, Elekta
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
I can’t see the tumor The tumor moves The patient is breathing The patient is fidgety
Add margin Add margin Add margin Add margin
Circa 1985
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
What we can see vs.
what we treat
UNC
UNC
2D
3D in our “heads”
UNC
Gross Tumor Volume (GTV)
Microscopic Spread
Set-up Errors + + Internal
Motion +
Grouped Uncertainties: 1.5-2.0 cm margins
UNC
Gross Tumor Volume (GTV)
Microscopic Spread
Set-up Errors + + Internal
Motion +
Imaging- CT, PET
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3D, Beams Eye View (BEV)
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Conformally-shaped field
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UNC
CT
MR
PET
UNC
95% iso-dose line
UNC UNC
PET for Lung Cancer
Munley (1996) 34% (12/25) Kiffer (1998) 27% (4/15) Nestle (1999) 35% (12/34)
Rate of Change in CT-Defined GTV
UNC
Gross Tumor Volume (GTV)
Microscopic Spread
Set-up Errors + + Internal
Motion +
Imaging- CT, PET
Fancy “Imaging”
Respiratory gating/control
UNC UNC UNC
UNC UNC http://www.mcw.edu/display/docid1797.htm
Cone Beam CT Scanner
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UNC UNC UNC
CT-on-Rails system at UNC
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UNC
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Tools
UNC
Tools: IGRT and Motion Management
IGRT: Pre-RT IGRT: During-RT Motion
Linac 3D (Cone beam, CT on rails)
2D plannar (not 3D)
Gating “ITV”
(internal target
volume CyberKnife 2D plannar 2D plannar tracking
Tomotherapy 3D (MVCT) ?
Gamma Knife - -
UNC
Gross Tumor Volume (GTV)
Microscopic Spread
Set-up Errors + + Internal
Motion +
Calypso
UNC
What is Calypso? • Non-radioactive • Implantable
fiducial • No power source in
seeds
Images from www.calypsomedical.com
UNC
Electromagnetic field
Images from www.calypsomedical.com
UNC
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
UNC
IMRT
Intensity modulated radiation therapy
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Conventional/3D
All beams cover all of target
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95% iso-dose line
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95% iso-dose line
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95% iso-dose line
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F F
Bladder
Rectum
Prostate
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F F
Bladder
Rectum
Prostate
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F F
Bladder
R
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F F
Bladder
R
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F F
Bladder
R
Uniform Intensity
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IMRT
Intensity modulated radiation therapy
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F F
Bladder
R
compensator
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F F
Bladder
R
Compensator: Modulates beam Intensity
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F F
Bladder
R
compensator
One beam: heterogeneous prostate dose
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One beam: heterogeneous dose
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F F
Bladder
R
Multiple beams: adds up ok
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Avoiding Spinal Cord
Dose ‘bending” with IMRT
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Almost Magic
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Integral Dose • Total energy deposited in patient
Units: gram-rad (gram) (energy/gram) = energy
• Hypothesis: Integral dose is largely constant for IMRT vs. 3D
IMRT redistributes dose
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100
100 50 50
50
50
33
33
33 33
33 33
Intuitively correct. Non-divergent beams. No attenuation. Dose must go somewhere.
100 100
Symmetric: orientation irrelevant
(a la Mike Goiten)
UNC Modified from Chapet et al. IJROBP 65:261, 2006
Mean Lung Doses (Gy): Univ. Michigan
Case 1 2 3 4 5 6 7 8 3D conformal 20.0 10.2 12.9 18.0 12.8 16.6 10.5 9.1 Same orientation IMRT
19.8 10.5 12.2 18.4 12.6 16.6 12.5 8.3
3F IMRT 20.0 10.6 11.8 18.0 13.4 16.7 12.6 9.1 5F IMRT 19.6 10.6 11.5 18.0 13.6 16.7 12.1 9.3 7F IMRT 20.1 10.6 12.4 18.1 11.2 16.6 11.0 8.9 Average 20 11 12 18 13 17 12 9 % STD Deviation 1 2 4 1 7 <1 8 4
UNC
UNC
Dose ‘bending” with IMRT
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
UNC Univ North Carolina
Pneumonitis, mean dose response - whole lung
Mean dose (Gy)0 10 20 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0MSKCC (10/78)Duke (39/201)Michigan (17/109)MD Anderson (~49?/223)NKI (17/106)WU (52/219)Martel et al. (9/42)Oeztel et al. (10/66)Rancati et al. (7/55)Kim et al. (12/68)logistic fit
Objective data review: Jackson, Deasy, Martel, Bentzen 1,167 pts NSCLCa, 9 centers
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
UNC
PORT: post-op RT
Two studies NOT in the PORT meta-analysis
UNC UNC
No Further Tx
Tradella (Italy) Radio Oncol 62:11, 2002
Small-field / conformal RT
≥ Lobectomy + Nodal Resection (Median 20 nodes sampled)
104 pts pathologic T1-2 N0
Randomized
P=0.046
Overall Survival
UNC UNC
PORT Randomized Trial: Stage 1-3 (T1-3, N0-2) NSCLC: Overall Survival (N=155)
Mayer. Chest 112:954, 1997 (Austria)
Surgery Alone
Surgery + RT (3D/CT planning, 50-56 Gy)
Months
Not Sig: HR for death 0.85 (CI 0.66-1.09)
UNC
3D Planning Improves Therapeutic Ratio
UNC
Fractionation depends on normal tissue within field
Conformal
Radiosurgery
IMRT
reduces normal tissue in field
need to spare normal
tissue with
fractionation
Better tumor imaging (e.g., PET)
UNC
Metastases Body RS
Can SBRT yield local control?
Author N Median Follow-up
(months) Local Control
Liver Mets: Rusthoven (2009) Univ CO-Denver 47 16 1 year 95%
2 year 92% Lee (2009) Univ of Toronto 68 10.8 1 year 71% Vautravers-Dewas (2011) Lille, France 42 14.3 1 year 90%
2 year 86% Brain Mets: Minniti (2011) Univ “La Sapienza,” Rome 206 9.4 1 year 92%
2 year 84% Wegner (2011), Univ Pitts
44 9 1 year 86%
Oligo-Mets: Milano (2011) Univ Rochester 121 54 (breast),
19 (non-breast) 2 year 87% 2 year 74%
UNC
Milano. Cancer ‘08; 112:650.
Milano IJROBP 2008, 72(5): 1516-22.
Overall Survival
Progression Free Survival
28% @ 4 yrs
SBRT Oligo Mets(≤5) Prospective Study 2001-7; 121 pts 293 treated lesions Courtesy of Dr. Mike Milano, Univ Rochester
Lesion Local Control 73% @ 4 yrs
Rate
UNC Salama …. Hellman, Weichselbaum. Cancer 2011.
SBRT for Oligo Mets (1-5) Prospective Study 2004 - 09; 61 pts with; 113 mets < 10 cm;
Time (months)
Percentage
Overall Survival
82% @ 1 yr
57% @ 2 yrs
Dose escalation 8 Gy x 3….. 16 Gy x 3
UNC
Can we cure patients with metastatic cancer?
RT for lesions we see
Chemo for lesions we cannot see
UNC
Reasonable to consider aggressive local therapy
for mets
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Normal Tissue Imaging
UNC
SPECT lung perfusion scan: 3D distribution of function
UNC
Duke McGuire et al. IJROBP 66:1543-1552, 2006
CT Plan
SPECT Plan
PTV
PTV
IMRT- reduce dose to functional lung (SPECT guidance)
Boost
Boost
UNC
Proton
UNC UNC
Over-Reliance
on Imaging
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Field Margins
Certainty of Gross Anatomy
Physically or biologically necessary margin
More conservative approach
Too fancy: marginal miss
UNC UNC UNC
Method Margins (mm)
Biochemical Disease Free
Survival (5yrs)
P- Value
Implanted Seeds for Localization (N = 25)
3-5 58% 0.02
No Implanted Seeds (N =213) 6-10 91%
Prostate: Too Fancy?
Engels, IJROBP 74:388, 2009
UNC
Gross Tumor Volume (GTV)
Microscopic Spread
Set-up Errors + + Internal
Motion +
Addressing physical uncertainties unmasked biological ignorance
Cancer spreads microscopically
Add margin Add margin Add margin Add margin
Circa 1985
I can’t see the tumor The tumor moves The patient is breathing The patient is fidgety
UNC
PET, CT.. 4D CT.. Gating..
Calypso..
Circa 2012
I can’t see the tumor The tumor moves The patient is breathing The patient is fidgety
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Improved therapeutic ratio
•e.g. post-op RT, radiosurgery, oligometastases •Shortcomings
•Unmasking biological uncertainties •Increased complexity, safety issues
Uncertainty Margins
UNC UNC
• Rebecca Green • Adam Willson • Mike Milano, Univ. Rochester • Dorothy Riguera • David Fried • Mark Kostich • Michael Lawrence • Brian Kavanagh, Univ Colorado • David Morris • Julian Rosenman
Acknowledgments
UNC
Summary
Reduced uncertainty
(e.g. imaging tumor location, motion)
Better predictors of normal tissue
risks
Control of dose Delivery (e.g.
IMRT, Radiosurgery)
•Tighter margins, more conformality •Less normal tissue in field •Less need to fractionate
•Hypofractionation, radiosurgery
Uncertainty Margins
