perils of proton therapy

Perils of Proton Therapy

Jatinder R Palta PhDUniversity of Florida

Department of Radiation OncologyGainesville, Florida

Are there any issues with these illustrations?

J Johansson PhD Thesis 2006

Siemens Particle Therapy 2007

Proton spot scanning (from PSI home page, Pedroni et al)

Yes, they have made Proton Therapy prone to hyperboleprone to hyperbole

“Proton therapy can strike a tumor with millimeter accuracy, yet spare healthy tissue around the tumor and cause very few, if any, side y y , y,effects. In the Proton Therapy Center, we’re able to deliver energy like never before.”

“It sounds like power belonging only to a superhero: a high-powered beam that is able to zap a millimeter area within someone’s body,beam that is able to zap a millimeter area within someone s body, and yet not harm the surrounding healthy cells. Heroic — yes, but this is not in comic books. It’s happening in real life, in nearby XXXXXX.”

“When treated with Proton Beam Therapy radiation is controlledWhen treated with Proton Beam Therapy, radiation is controlled while inside the body, that enables the physician to deliver full or higher doses while sparing surrounding healthy tissues and organs. It allows to deliver necessary dose of radiation without causing damage to healthy tissues ”causing damage to healthy tissues.

“With protons.. energy can be very precisely controlled to place the Bragg peak within a tumor or other tissues that are targeted to receive the radiation dose. Because the protons are absorbed at this point normal tiss es be ond the target recei e er little or nopoint, normal tissues beyond the target receive very little or no radiation”.

Promises of Proton TherapyCompared to external beam photon therapy,proton therapy:proton therapy:• Decreases the integral dose due to the “finite range” of

protons• Reduces the volume of normal tissue exposed to low

doses, potentially lowering the risk of second malignancies This risk is notably higher for youngmalignancies. This risk is notably higher for young patients, as they are more at risk to future radiation induced cancers.

• Has demonstrated advantage for treating small tumor volumes at shallow depths (eye tumors and CNS such as chordomas and chondrosarcomas)chordomas and chondrosarcomas)

• Has demonstrated advantage for treating a few select cases in almost all disease site

Perils of Proton TherapyPerils of Proton Therapy1. Uncertainties:

C f l i i ( ) Consequences of nuclear interactions (neutrons) Multiple Coulomb scattering (lateral penumbra) Intrinsic basic physics uncertainty (I-values)

CT numbers (stopping powers; range) CT numbers (stopping powers; range), Dose calculation errors due to complex inhomogeneities, Intra-fractional organ motion, Inter-fractional changes in anatomy and motion patterns Inter fractional changes in anatomy and motion patterns, Mis-registration of tissue compensators (passively

scattered proton beams, Uncertainties in immobilization devices and patient

support devicessupport devices2. Evaluation of proton plans

How to evaluate a proton plan in the presence of various uncertainties?uncertainties? PTV? Error bars of dose distributions?

Nuclear InteractionsAbout 20% (~1%/g cm-2)of primary protons lost to interactions with

Effect on the lateral dose distribution

Effect on the depth dose curve

About 20% ( 1%/g.cm )of primary protons lost to interactions with atomic nuclei

Pristine Bragg peak

Secondary ti l fl

Proton fluenceparticle fluence resulting from nuclear interactions

Primary fluence

Resultant Bragg peak

Lomax : AAPM SS 2003

Proton Scattering

= f(w) = f(w)ips

3

Gy)

A proton pencil beam

t t = f(i MCS )4

5

mm

)

2

se p

er p

roto

n (n

G tot = f(ips, MCS )

2

3

4

igm

a M

CS

(m

MCS (80-20%) lateral dose fall-offs at 10cm depth

0 5 10 15 20 250

1

Depth in water (cm)

Dos

1Si Protons – 5-8mm

6MV photons – 6mm

p ( )


Proton Depth Dose (PDD)p ( )

3

y) Peak-to-plateau

2

r pro

ton

(nG

y

Width of peak dependent on

range straggling in

pratio 3-5

(depending on width of energy

spectrum)

1

Dos

e pe

r

2)(1

dXdE

range straggling in medium and initial energy spectrum; typically 8 mm for

177 MeV p

p )

0 5 10 15 20 250

Depth in water (cm)

2c)(dX 177 MeV p

Depth-dose curve for 177 MeV protons

PDD as a function of SOBP widthsG2_250MeV_RMW91_range28.5cm_mediumsnout@5cm

1201 Excitation/ionization;

80

100 121

2

Excitation/ionization;Nuclear interaction

Excitation/ionization (Bragg Peaks);Nuclear interaction

40

60

PDD SOBP 4 cm, Measured 4.2 cm

SOBP 10 cm, Measure 10.2 cmSOBP 16 cm Measured 16 1cm

33

4

Range straggling and energy spread

Neutrons from nuclear i t ti

0

20

40 SOBP 16 cm, Measured 16.1cmSOBP 12 cm, Measured 12.0 cmSOBP 8 cm, Measured 8.1 cmSOBP 6 cm, Measured 6.1 cm 4

4 interactions

00 50 100 150 200 250 300 350

Depth (mm)

,SOBP 14 cm, Measured 14.3 cm

Note increase in entrance dose with increase in modulation.

Intrinsic basic physics uncertainty (I l )

4

Protons on waterP122 Iw67P122 Iw75cl

e

(I-values)

3

Protons on water I

w- dependenceP122 Iw80

P183 Iw67P183 Iw75P183 Iw80P230 Iw67de

nt p

artic

The peak spread increases with energ

2

P230 Iw75P230 Iw80

2 ) per

inci

d energy

1MeV

/g c

m2

0

dE/d

z (

00 5 10 15 20 25 30 35

depth in water (g/cm2)P Andreo, Phys Med Biol, 2009

4122 MeV Protons on water: I

w- dependence

P122 I = 67eVle0.3 g/cm2

3

w

P122 Iw = 75eV

P122 Iw = 80eV

ent p

artic

l

2) per

inci

d

1MeV

/g c

m2 )

1

dE/d

z (M Peak spread is .7 g/cm2

for 230 MeV protons

09.5 10.0 10.5 11.0 11.5

depth in water (g/cm2)Intrinsic basic ph sics ncertaint makes the

P Andreo, Phys Med Biol, 2009

Intrinsic basic physics uncertainty makes the argument of “sub-millimeter precision” an issue, which deserves careful consideration

MUSCLE SKELETAL (ICRP)

average I-values of various soft tissues

TESTES (ICRP) WATER LIQUID BLOOD (ICRP) LUNG (ICRP) MUSCLE SKELETAL (ICRP)

GI TRACT (INTESTINE)HEART ADULT (HEALTHY)MUSCLE STRIATED (ICRU) HEART ADULT (BLOOD-FILLED)TISSUE SOFT (ICRU-33 4 comp)

UREA BRAIN (ICRP) EYE LENS (ICRP) HEART ADULT (FATTY)GI-TRACT (INTESTINE)

BREAST (WHOLE)-50/50TISSUE SOFT (ICRU-44 FEMALE)TISSUE SOFT (ICRU-44 MALE)TISSUE SOFT (ICRP) SKIN (ICRP)

62 64 66 68 70 72 74 76ADIPOSE TISSUE (ICRP) BREAST (WHOLE)-33/67BREAST (WHOLE) 50/50

I-value (eV)I-value (eV)


3 0

164 MeV protons on various tissues(+/- 10% change in I-values)

2.5

3.0pa

rtic

le 0.7 g/cm2

Peak spread assuming 10% uncertainty

2.0

r inc

iden

t p in I-values

1.0

1.5

P 164 muscle skeletal ICRPcm2 /g

) per

0.5

1.0P 164 tissue soft ICRU-44 F

P 164 water (I=75)

P 164 muscle skeletal ICRP

E/dz

(MeV

c

0.017.0 17.5 18.0 18.5 19.0 19.5

P 164 tissue soft ICRU-44 FdE

depth (g/cm2)depth (g/cm )


HU-Stopping Power Calibration Curve

1 6

1.8

2e

r

1

1.2

1.4

1.6

pp

ing

Po

we

0.6

0.8

1

ea

lati

ve

Sto Large phantom, Average position, 140kV,

400mAs, Big bore

Body phantom, Average position, 140kV,400mAs, Big bore

Full head phantom Average position 140kV

0

0.2

0.4

-1000 -500 0 500 1000 1500 2000

Re Full head phantom, Average position, 140kV,

400mAs, Big boreEmpty head phantom, Average position, 140kV,400mAs, Big bore

1000 500 0 500 1000 1500 2000

CT # S. Flampouri, UFPTI

Range uncertainty due to CT calibration is g ygenerally taken as 3.5%. However, it can be minimized with better calibration techniques.

HU‐Stopping Power Conversion Uncertainties Results in Range UncertaintiesResults in Range Uncertainties

S Flampouri, UFPTI, 2007

Impact of CT Hounsfield number uncertainties on dose distributionsuncertainties on dose distributions

-3.5% +3.5%

Dong/MDACC

0% uncertaintyIndividualized patient determination of tissue composition along the complete beam path rather than CT Hounsfieldalong the complete beam path, rather than CT Hounsfield numbers alone, would probably be required even to reach “sub-centimeter precision”

CT Artifacts and Hounsfield Numbers

“It is imperative that body-tissue compositions are not given th t di f h i l t t d th i t dthe standing of physical constants and their reported variability is always taken into account” (ICRU-44, 1989).

Proton treatment deliveryPassive scattering in practicePassive scattering in practice

Aperture Compensator

Range modulator wheel

Scatterer

Target

Patient

Range compensator conforms dose to distal edge target volume; the aperture shapes field in lateralshapes field in lateral direction.

Brass aperture Lucite range compensator

Misalignment of the compensator g pwith Target Volume

Correct alignment of (c)(b)(a) (c)(c)(b)(b)(a)(a)Correct alignment of the compensator and target volume

Patient is shifted left

Patient is rotated clockwise

ICRU Report 78

Proton Range Uncertainty in the Presence of heterogeneitiesPresence of heterogeneities

Soft tissue Rhomtissue Rhom

Soft tissue

Bone

Rinhom


Impact of Organ Motion on Proton Dose Di ib iDistributions

Free breathing treatment

Tsunashima/MDACC

Dong: ASTRO 2008

Impact of Organ Motion on ProtonImpact of Organ Motion on Proton Dose Distributions

Prescription Dose Line

Treatment planned based on single Free-breathing

The same treatment plan calculated on 4D CTon single Free breathing

(FB) CT image (conventional approach)

calculated on 4D CT images

Y. Kang et al. IJROBP. 67, 906-914 (2007)

Comparing Proton Therapy with IMRT

Protons TherapyProtons Therapy

Ca Oropharynx Photon IMRTYeung UFPTI

Ca Oropharynx Concomitant Boost (7200 cGy)

PROTONSPhoton IMRTTumor Coverage

Concomitant Boost (7200 cGy)(95% PTV receives prescription dose, 99% PTV receives 93% of prescription dose and 20% PTV receives <110% of prescription dose)

6975 (96.7%)7221 (100.3%)99% of PTV 5400/7200

7178 (99.7%)7320 (101.6%)95% of PTV 5400/7200

PROTONSPhoton IMRTTumor Coverage

7243 cGy (106%)7722 (107.3%)20% of PTV 5400/7200

26855020Brain stem (0.1 c.c.)

14822529Contralateral parotid(mean dose 2600)

5464400Spinal cord (0.1 c.c.)

61486928Contralateral submandibular gland (mean dose 2600)

Yeung UFPTI

Please note that this is ONLY a synthetic comparison of two modalities of treatment

The Clinical ChallengegAccurately deliver ionizing radiation to the real

dynamic patienty p

Intra‐Fraction Prostate Motion Due to Breathing and Bladder FillingDue to Breathing and Bladder Filling

Rectal DVH from multiple post treatment PET/CTp p /

70 00

50.00

60.00

[email protected]

rectumRAO#[email protected]



[email protected]

Uncertainties in Rectal V74and V39

30.00

40.00

Volu

me

(%)

rectumLAO#[email protected]



and V39

Mean ±Dev.

Rel. Dev. ±Dev.

10.00

20.00 V74 9.6%±7.2% 73.9%±20.5%

V39 25.2%±11.4% 42.1%±15.3%

0.0010 20 30 40 50 60 70 80 90 100 110

Dose (%)

39

Yin: UFPTI, 2008

Anatomic Variations During Course of RT

Barker et al. Int J Radiat Oncol Biol Phys 2004;59:960-970Biol Phys 2004;59:960-970.

Planning CT Three Weeks into RT

D l l t d

Impact of Tumor Shrinkage on Proton Dose DistributionOriginal Proton Plan

Dose recalculated on the new anatomy

ose st but o

Bucci et al. ASTRO Abstract, 2007

The three ‘orders’ of proton therapy compared

Intensity Modulated Proton Therapy (IMPT)

IMPTPassive scattering

Spot scanning

e t ee o de s o p oto t e apy co pa ed

1 field1 field 1 field

3 fields3 fields 3 fieldsLomax/PSI

Plan DVH Evaluation (PTV)

Photon DVH

What you see is not what you always get….um

e

Proton DVH

Vol

Dose

Plan DVH Evaluation (PRV)What you see is not what you always get..

me

Proton DVH

Volu

m

Photon DVH

Dose

Plan EvaluationWhat you see is not what you always get….

IMXT Plan IMPT Plan(with Confidence-weighted Isodose Distribution)

Lomax PSI

Ji UFThere is no easy way to

180 160 120 80 40 cGy

Jin UFy y

show what patient will get in proton therapy

Summary 1• Proton beams stop ‐ no exit dose

Although we don’t know exactly where they stop– Although we don t know exactly where they stop

• Proton beams are more sensitive to

– CT Hounsfield number/Stopping Power accuracy

– Organ motionOrgan motion

– Anatomy changes

• Proton plans are difficult to evaluate

– “What you see is not what is delivered”y

• Protons demonstrate excellent low dose sparing

Summary 2• IMPT shows additional benefits both in low

dose sparing and high dose conformalitydose sparing and high dose conformality

• IGRT and Adaptive RT will play an important

role• Inter/Intra‐fractional variations have far moreInter/Intra fractional variations have far more significant consequences in patients treated with proton therapyp py– Approaches and data to deal with this issue is still lacking

• Minimize it and develop strategies to deal with the residual motion

Summary 3Summary 3

• Empirical approaches used in defining margins for• Empirical approaches used in defining margins for range uncertainties, smearing, and smoothing are questionableq– No real data exist to support any of these approaches

• Repeat imaging and reevaluation based on p g gdeformable registration may be necessary– In some cases repeat planning may be clinically beneficial

• Biologically Effective Dose– Little published data on end of range RBE

General Observations Regarding P t Th T h lProton Therapy Technology

• State‐of the Art in Proton Therapy is still an accelerator with multi‐room configuration and scattered beam delivery system. These are far from “turnkey” systems

•– Scanning and IMPT are still a works‐in‐progressScanning and IMPT are still a works in progress.– Subsystem integration is far from complete

• It impacts clinical workflow and throughput

• Development of new proton beam production technologies are being f l d b th i f t th i l ti ifueled by the promise of proton therapy in normal tissue sparing.– Developing a technology is lot simpler and quicker than its seamless and safe

integration in existing clinical work flow.• Historically, routine application of new developments in radiation oncology has

taken at least 5 years from the time its FDA approval (e g MLC IMRT IGRT etc )taken at least 5 years from the time its FDA approval (e.g. MLC, IMRT, IGRT, etc.)

• Promise of Proton Therapy will only hold if we take the most advantage of the state‐of‐the art in conventional radiation therapy– We must not be satisfied with less than the best in technology available for

i bili i i i l i i / i iimmobilization, imaging, treatment planning, patient/target position verification, and treatment delivery.

perils of proton therapy

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