evolution of novel radiation strategies to improve ... · evolution of novel radiation strategies...

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

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2D

3D in our “heads”

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Gross Tumor Volume (GTV)

Microscopic Spread

Set-up Errors + + Internal

Motion +

Grouped Uncertainties: 1.5-2.0 cm margins

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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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CT

MR

PET

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95% iso-dose line

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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

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Gross Tumor Volume (GTV)

Microscopic Spread

Set-up Errors + + Internal

Motion +

Imaging- CT, PET

Fancy “Imaging”

Respiratory gating/control

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UNC UNC http://www.mcw.edu/display/docid1797.htm

Cone Beam CT Scanner

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CT-on-Rails system at UNC

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Tools

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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 - -

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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

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Electromagnetic field

Images from www.calypsomedical.com

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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

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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

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Dose ‘bending” with IMRT

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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

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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)

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3D Planning Improves Therapeutic Ratio

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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)

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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

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Can we cure patients with metastatic cancer?

RT for lesions we see

Chemo for lesions we cannot see

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Reasonable to consider aggressive local therapy

for mets

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Normal Tissue Imaging

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SPECT lung perfusion scan: 3D distribution of function

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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

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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

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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