Heavy charged particles for cancer radiation therapy

(HST.187)Introduction (Bragg peak, LET, OER, RBE)

I. Physical rationale

II. Biological rationale

III. Clinical rationale

This document: http://gray.mgh.harvard.edu/ (Resources)

Proton Therapy Facilities

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Worldwide proton therapy experience

Proton Therapy Facilities

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exponential

Moore’s law of proton therapyExponential growth:Factor 2 in 10 years

Hospitals Chase a Nuclear Tool to Fight Cancer

Front page, December 26, 2007

There is a new nuclear arms race under way — in hospitals. Medical centers are rushing to turn nuclear particle accelerators, formerly used only for exotic physics research, into the latest weapons against cancer. Some experts say the push reflects the best and worst of the nation’s market-based health care system, which tends to pursue the latest, most expensive treatments — without much evidence of improved health — even as soaring costs add to the nation’s economic burden…

Recommended reading

I. Physical rationale- The concept of dose -• Dose is a measure of the amount of energy

deposited in a small volume at a point of interest as a result of the radiation - be that energy deposited locally, or brought to the point of interest by secondary radiation generated at some distance from the primary interactions.

• The dose is the energy deposited in a small volume divided by its mass.

• Dose is expressed in units of Gray (Gy)• 1 Gy = 1 Joule/kg

Bragg peak

Depth

Do

sePhotons

Protons

Spread-Out Bragg Peak (SOBP)

100%

60%

10%

PROTONS

PHOTONS

Medulloblastoma

“dose bath”

The proton advantage:Nasopharynx

Photons (IMRT) Protons

Dose bath

The proton advantage:Paraspinal

Photons Protons

Dose bath

I. Physical rationale

• Why charged particles?

• Why heavy?

I. Physical rationale

• Heavy charged particle therapy can reduce the dose load (“integral dose”) to normal tissues surrounding the tumor target volume by a factor of 2-3 (reduced “dose bath”).

• Increased “dose conformality”, i.e., dose gradient between tumor target volume and surrounding healthy tissues.

II. Biological rationale

• Recommended reading:– Eric J. Hall, Radiobiology for the Radiologist,

Lippincott, 2000– Chapter 5 in Goitein– Chapter 2 in DeLaney/Kooy– N. Suntharalingam, E.B. Podgorsak,

J.H. Hendry: Basic RadiobiologyIAEA publicationshttp://www-naweb.iaea.org/nahu/dmrp/pdf_files/Chapter14.pdf

II. Biological rationale

Linear energy transfer (LET)

“LET of charged particles in a medium is the quotient dE/dl, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dl.”

●250 kVp X rays: 2 keV/μm.

●Cobalt-60 rays: 0.3 keV/μm.

●3 MeV X rays: 0.3 keV/μm.

●1 MeV electrons: 0.25 keV/μm.

—14 MeV neutrons: 12 keV/μm.

—Heavy charged particles: 100–200 keV/μm.

—1 keV electrons: 12.3 keV/μm.

—10 keV electrons: 2.3 keV/μm.

LET < 10 keV / m low LETLET > 10 keV / m high LET

Oxygen enhancement ratio (OER)

well oxygenated

well oxygenated

hypoxic

hypoxic

LET and OER

The linear-quadratic model of cell kill

S(D) is the fraction of cells surviving a dose D;

is a constant describing the initial slope of the cell survival curve;

is a smaller constant describing the quadratic component of cell killing.

2

)( DDeDS

The linear-quadratic model of cell kill, fractionation

From cells to organs, dose-volume effects

“Bath and shower” experiment on rat spinal cordBijl et al, IJROBP 57:274-281, 2003

From cells to organs, dose-volume effects,Equivalent Uniform Dose (EUD)

Tumor Control Probability (TCP),Normal Tissue Complication Probability (NTCP)

Schematic diagram on how the EUD can be used to estimate TCP

What is the difference inbiological effectiveness betweenparticles and photons/electrons ?

Considering RBE

Relative Biological Effectiveness (RBE)

Dosis

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RBE=Dx/Dp

Definition of RBE

X-rays

Particles

Dose per fraction [Gy]

1 10

RB

E

0.5

1.0

1.5

2.0

2.5

1.07 0.12

RBE values for protons, in vivo (center of SOBP; relative to 60Co)

• Mice data:• Lung tolerance, Crypt regeneration, Acute skin reactions,Fibrosarcoma NFSa

RBE values

• RBEgeneric = 1.1 for protons • RBE for heavier particles (carbon ions) can be

much higher (>3)

• RBE dependencies:

– Endpoint: RBE (, survival/mutationin vitro/in vivo)

– Dose: RBE increases with decreasing dose (in vivo ?)

– LET: RBE clearly increases with depth

LET and RBE, “overkill”

Clinical potential of proton therapy:

• Reduce side effects (reduce NTCP)

• Increase tumor control probability (TCP) through “dose escalation”

• Facilitate combined modality therapy– Radiation+chemo, Bevacizumab, …

• Easy re-treatment of disease– Make cancer a chronic disease

• …

Physics projects in proton radiotherapy

1. Range prediction• Finite range is the primary feature of proton therapy• Range in the patient is uncertain• Better dose calculation models needed

2. New challenges in image-guided RT (IGRT)• Impact of image artifacts on proton range • Impact of weight loss, tumor shrinkage• Adaptive planning essential

3. Intensity modulated proton therapy (IMPT)• Beam scanning techniques• Challenging optimization problems

Physics projects in proton radiotherapy

4. From margins to robust plan optimization• PTV concept does not work in proton therapy

5. Unique potential for in-vivo measurements• Positron activation – PET/CT measurements• Spontaneous gamma production

6. Develop new/cheaper acceleration techniques• Laser acceleration, DWA• Collaborate with laser and plasma physicists

7. Biological modeling• Essential in C-12 therapy• New fractionation schemes

Feb 5 Introduction: Physical, biological and clinical rationale Bragg Peak, LET, OER, RBE

T. Bortfeld

Feb 12 Acceleration of charged particles Standard techniques (with demonstration) Laser acceleration Dielectric wall acceleration

J. Flanz

Feb 19 Making a useful treatment beam beam line and “gantry” scattering system, collimation magnetic beam scanning

B. Gottschalk

Feb 26 Interactions of charged particles with the patient B. Gottschalk, T. Bortfeld

Mar 4 Neutrons in particle therapy Neutrons as a by-product of charged particle therapy Biological effects Neutron therapy

H. Paganetti

Mar 11 Biological aspects of particle therapy H. Paganetti Mar 18 Spring break (HMS) Mar 25 Spring break (MIT) Apr 1 Imaging for charged particle therapy

Image guided procedures In-vivo dose localization through imaging

H.-M. Lu

Apr 8 Treatment planning for charged particle therapy Dose computation Issue of motion Practical demonstrations at MGH

M. Engelsman

Apr 15 Clinical treatments Apr 22 Dosimetry and quality assurance M. Engelsman Apr 29 Intensity-modulated particle therapy T. Bortfeld May 6 Treatment with heavier charged particles May 13 Special topics and wrap-up

Summary

• Physical rationale of heavy charged particle therapy– Reduced integral dose (by factor 2-3)

– Potentially improved dose conformality

• Biological rationale: – Based on modeling studies: LET, OER, EUD,

TCP/NTCP, RBE

– Potentially increased RBE, but only for heavier particles (heavier than protons)

• Clinical rationale:– Do we need randomized clinical trials?

Homework assignment

1. If every radiation therapy patient worldwide* would get proton therapy (instead of x-rays), what would be the annual dose reduction in healthy tissues compared with the dose load from the Hiroshima bomb?

2. Read (and understand) the short review of radiation biology fromhttp://www-naweb.iaea.org/nahu/dmrp/pdf_files/Chapter14.pdf

*Assume that there are 2 million patients receiving x-ray radiation therapy every year

Dose     Distance (km)

    Hiroshima (mGy)

    Nagasaki (mGy)

Gamma ray

0.51.01.52.0

35,7004,220

54981

83,0008,620

983138

Neutron

0.51.01.5

2.0

6,480260

90.4

2,970125

50.2

Total number of people exposed: Hiroshima: 350,000; Nagasaki: 270,000 Source: Hiroshima international council for healthcare of the radiation exposed