06/03/2018

Alternative Radiation Modalities

Dr. Konrad Leszczynski

with slides from Dr. Oliver and Dr. Wan

LU: PHYS 3306 EL - Radiobiology & Radiation

Protection: March 6, 2018

Agenda
Chapter 25 in Radiobiology for the Radiologist 7th Ed by Hall & Giaccia
•Review: LET, OER, RBE, Radiation Weighting Factors
•Fast Neutron Therapy
•Boron Neutron Capture Therapy
•Proton Therapy
•Carbon Ion Therapy
•Summary of Pertinent Conclusions

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Accelerators ‐ cyclotrons

Accelerators ‐ synchrotrons

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Linear Energy Transfer (LET)

•LET – refers to the average energy transferred to
tisssue per unit length by an ionizing particle in units
of keV/m
MV x-rays (0.3 keV/m)

kV x-rays (2 keV/m)
10 MeV
proton beam (4.7 keV/m)

290 MeV Carbon ions

(40‐90 keV/m)

Relative Biological Effectiveness

(RBE)
• RBE – refers to the ratio of the
dose of 250 keV required for a
given effect compared to a
different type of radiation. The
greatest RBE for cell‐killing occurs
at 100 keV/m.

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Oxygen Enhancement Ratio (OER)

•OER – refers to the ratio of the dose necessary to
provide an effect under anoxic conditions divided by the
dose necessary to produce the same effect under oxic
conditions.
– At low LET (photons) OER is 2.5‐3.0 as reflected by the oxygen
required to produce DNA damage
– At high LET (charged particles) OER approaches 1.0 since most
damage is direct and oxygen‐independent

OER, RBE and

LET

290
X‐rays
(kV‐MV MeV
10 MeV Carbon
ions
range)

Protons

Hall, Fig 7.10

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Percent Depth Dose Curves

Introduction
Currently, great majority of external beam radiotherapy is
carried out with megavoltage X‐rays, and to some degree with
MeV electrons.
In a few specialized centres external beam radiotherapy
utilizes also heavier particles, such as:
•Neutrons
•Protons
•Heavy ions (helium, carbon, nitrogen, argon, neon) produced
by cyclotrons and synchrotrons.

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Summary of Radiobiological
Properties of Radiation
Beams X‐Rays Fast
Neutrons
Protons He Ions C Ions

Pseudo‐ Pseudo‐ Bragg Peak Bragg Peak Bragg Peak

Attenuation exponential exponential
with depth
Average RBE 1 1 1.1 1.4 3

Average OER 2.5 2.5 2.4 2.3 1.7

Integral high highest low lower Lowest

Dose
Everywhere none ~60 centers ~none ~10 centers
Availability worldwide worldwide

Neutrons

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Fast Neutrons
Neutrons were first used at the Lawrence
Berkeley Laboratory in California in the
1930s.

Fast Neutrons
Dr. Robert Stone, the oncologist in
charge of the study (1948):
“Neutron therapy as administered
by us resulted in such bad late
sequelae in proportion to a few
good results that it should not be
continued.”

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Neutrons at the Hammersmith

Hospital (London, UK)
• Neutrons were generated by 16‐MeV
deuterons from a cyclotron, incident on a
beryllium target (modal neutron energy of
6 MeV).
• Poor depth‐dose characteristics.
• Neutron treatments were clearly superior
in terms of local control, but had higher
complication rate.

Neutrons – US Experience
•Large cyclotrons that accelerate deuterons
to energies of 22 to 67 MeV – improved
depth dose characteristics.
•Several clinical trials showed no advantage
for neutrons over x‐rays.
•Neutrons showed some advantages for
salivary gland tumors, soft tissue sarcomas,
and prostate cancer, but at a price of a
significant late normal tissue damage.

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Boron Neutron Capture Therapy

(BNCT)
The idea:
• To deliver to the cancer patient
a boron‐ containing drug that is
taken up only in the tumour.
• To expose the patient to a
beam of low‐energy (thermal)
neutrons that will interact with
the boron and produce short‐
range, densely ionizing α‐
particles.

Boron Neutron Capture Therapy

(BNCT)
The problems:
• There is no wonder drug that
will selectively target tumour as
its destination.
• Thermal neutrons have poor
penetration in tissue leading to
poor depth dose distributions.

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Protons

Proton Beam Therapy ‐ History

•Robert Wilson (Harvard) in 1946 proposed that:
•With accelerators available protons can be used
clinically
•Maximum radiation dose (Bragg peak) can be placed
into the tumor and thus spare normal tissues
•Modulator wheels can spread narrow Bragg peak.

Wilson, R.R. (1946), “Radiological use of fast protons,” Radiology 47, 487.

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Proton Beam Therapy – Bragg Peak

Photons

Protons

Depth
http://gray.mgh.harvard.edu/

Proton Beam Therapy – Bragg Peak

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Proton Beam Therapy – Bragg Peak

http://gray.mgh.harvard.edu/

Proton Beam Therapy ‐

•
History
1946 R. Wilson suggests use of protons First
• 1954 treatment of pituitary tumors
• 1958 First use of protons as a neurosurgical tool
• 1967 First large‐field proton treatments in
• 1974 Sweden
Large‐field fractionated proton treatments
• 1990 program begins at HCL, Cambridge, MA
First hospital‐based proton treatment
center opens at Loma Linda University
Medical Center

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68 in Feb. 2018

Proton Beam Therapy ‐

Growth Proton Therapy
45 Facilities Exponential
40
operating
proposed growth: Factor 2 in
35
exponenti
al
10 years
30

25

20

15

10

0
1950 1960 1970 1980 1990 2000 2010 2020
Year
http://gray.mgh.harvard.edu/

Proton Beam Therapy ‐ S/C/SC* START

COUNTRY WHO, WHERE PARTICLE BEAM DIRECTIONS

Growth
MAX. ENERGY OF TREATMENT
(MeV)
MedAustron, Wiener
Austria p 2 fixed beams, 1 gantry 2017
Neustadt MedAustron, S 250
Wiener Neustadt
Austria TRIUMF, Vancouver C-ion S 430/u 2 fixed beams, 1 gantry 2017

Canada p C 72 1 fixed beam 1995

Particle therapy facilities in operation (last update: February 2017)
Czech Republic PTC Czech r.s.o., Prague
p C 230 3 gantries**, 1 fixed beam 2012
WPTC, Wanjie, Zi-Bo p C 230 2 gantries, 1 fixed beam 2004
China
IMP‐CAS, Lanzhou SPHIC, C-ion S 400/u 1 fixed beam 2006
China China China England France France
Shanghai SPHIC, Shanghai p S 250 3 fixed beams** 2014
Germany Germany Germany Germany Germany
Clatterbridge CAL/IMPT, C-ion S 430/u 3 fixed beams** 2014
Nice CPO, Orsay
p C 62 1 fixed beam 1989
HZB, Berlin RPTC, Munich
HIT, Heidelberg HIT, p C165, SC 235 1 fixed beam, 1 gantry 1991,
p C 230 1 gantry, 2 fixed beams 2016
Heidelberg WPE, Essen
PTC, Uniklinikum Dresden 1991,
p C 250 1 fixed beam
2014
MIT, Marburg p C 250 4 gantries**, 1 fixed beam
1998
p S 250 2 fixed beams, 1 gantry**
2009
C-ion S 430/u 2 fixed beams, 1 gantry**
2009,
p C 230 4 gantries***, 1 fixed beam 2012
2009,
Germany p C 230 1 gantry** 2012
2014
2013
3 horiz., 1 45deg. fixed
Germany p S 250 beams** 2015
3 horiz., 1 45deg. fixed
Germany C-ion beams** 2015
MIT, Marburg INFN‐LNS, S 430/u
Italy Italy pp 1 fixe beam 2002
Catania CNAO, Pavia
C 60 3 horiz., 1 vertical, fixed
2011
CNAO, Pavia APSS, Trento S 250 beams
HIMAC, Chiba 3 horiz., 1 vertical, fixed
beams 2012
Italy NCC, Kashiwa HIBMC, Hyogo C-ion S 480/u
2 gantries**, 1 fixed beams 2014
HIBMC, Hyogo PMRC 2,
Italy p C 230 horiz.***, vertical***, fixed
Tsukuba 1994
Japan C-ion beams
Shizuoka Cancer Center S 800/u
2 gantries*** 1998
Japan STPTC, Koriyama‐City pp C 235 •gantry horiz.,vertical, fixed 2001
Japan GHMC, Gunma C-ion S 230 beams 2002
Japan MPTRC, Ibusuki Fukui p p S 320/u •gantries*** 2001
Japan Prefectural p S 250 •gantries, 1 fixed beam 2003
Japan Hospital PTC, Fukui City S 235
C-ion •gantries**, 1 fixed beam 2008
Nagoya PTC, Nagoya
Japan S 235 •horiz., 1 vertical, fixed beams
City, Aichi SAGA‐HIMAT, Tosu p 2010
3 gantries***
Japan S 400/u
p 2011
Japan 2 gantries***, 1 fixed beam
S 250
2011
Japan
S 235
Japan
p S 250 2 gantries***, 1 fixed 2013
beam
Japan
C-ion S 400/u 3 horiz., vertical, 45 2013
deg., fixed beams
Japan Hokkaido Univ. Hospital PBTC,
Hokkaido p S 220 1 gantry 2014

Japan Aizawa Hospital PTC,

p C 235 1 gantry 2014
Nagano
i‐Rock Kanagawa Cancer
Japan
Center, Yokohama
C-ion S 430/u 4 horiz., 2 vertical, fixed 2015
beams

Japan Tsuyama Chuo Hospital,

p S 235 1 gantry 2016
Okayama
IFJ PAN, Krakow ITEP, Moscow p C 230 1 fixed beam, 2 gantries 2011,
Poland
St.Petersburg 2016
Russia p S 250 1 fixed beam 1969
Russia p S 1000 1 fixed beam 1975

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Proton Beam Therapy ‐ Growth

ProCure Proton Therapy Center, Somerst, NJ

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ProCure Proton Therapy Center, Somerst,

NJ
IBA C230 cyclotron
GE 16-slice 4D CT simulator
4 treatment rooms:
 1 Fixed Beam + 2 Incline Beam + 1 Gantry
~ 50 staff members
 4 radiation oncologists from Princeton Radiation
Oncology (1~2 on any given day)
 3 nurses
 Physics: 5 physicists, 1 assistant, 6 dosimetrists, 2 IT
 2 machinists + 1 facility manager
 10 radiation therapists
 2 intake personnel
 Marketing, billing, finance, etc

New York Proton Consortium (NYPC)

Plan to build a proton facility in NYC in 5~10 yrs
Collaborate with ProCure, NJ for now
5 institutions
 Memorial Sloan-Kettering Cancer Center
 New York University’s Langone Medical Center
 The Mount Sinai Medical Center
 Montefiore Medical Center
 Continuum Health Partners
19,000 patients receive radiotherapy per year * 3%
→
570/yr
25 radiation oncologists (15 faculty + 10 residents)
will treat at ProCure

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Scope of Patients
50~ 55 patients /day (4 shifts in 3 rooms)
~200 patients treated in the 1st year (spring

2012-13)
Disease sites: CNS (medulloblastoma), brain
(meningioma, chordoma), H&N (orbit,
mandible, maxilla, parotid, nasal cavity, acoustic
neuro, ethmoid sinus), lung, breast (incl. IMN),
lymphoma, abdo, GI (pancreas, liver, esophagus,
GE-j, etc), GU (prostate, bladder), GYNE
~40% prostate (decreasing)
Pediatric patients usually under daily general
anesthesia (external resource needed)

ProCure Arrangement with IBA

IBA:~10 employees (24/7)

IBA will supply, install and maintain
 Cyclotron
 Beam transport system
 Patient support devices (e.g. robotic PPS)
 In-room beam delivery systems (e.g. snout exchange)
8 to 16 treatment hours per day (Mon-Fri)
8 hours of beam time on Saturday (for physics

QA, etc)
IBA uses rest of the time for maintenance

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Fixed Beam Room

•Fixed proton beam angle (GA = 90º)

•Vertex cranial fields Prostate
•Pencil beam scanning (PBS)

Incline Beam Room

Robotic patient positioning system (PPS)

Two Beam Angles (GA = 30º & 90º)

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Treatment Chair

•Increase flexibility and improve utilization of

incline beam rooms to treat e.g. H&N, brain, etc.

Incline Beam Room (cont’d)

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Gantry Room

Gantry Room (cont’d)

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Anesthesia Bed

Timeline of an IBA Beam Allocation Cycle

delivering a treatment field requires a series of
operations/handshakes between the treatment room and the
cyclotron operator.
beam beam under ready for continuous segment
request tuning continuous beam beam
completed
TR process

IBA
process
beam ready for beam
allocate irradiatio de-
d n allocate
d
Event that is recorded by the ProCure queuing
system

switching tuning beam on

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Example of Beam Allocation

switching
TR1
tuning beam on
TR2

TR3 TR4

Combined

1 hour

Protons ‐ Advantages
•Heavy charged particle therapy can
reduce the dose (“integral dose”) to
normal tissues surrounding the tumor by
a factor of 2‐3 (less “dose bath”).
•Improved “dose conformality”, i.e., dose
gradient between target volume and
surrounding healthy tissues.

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Protons ‐ Advantages

Protons ‐ Advantages
•Reduction in side effects (NTCP↘);
•Increase in tumor control probability
(TCP↗) through “dose escalation”;
•Facilitatation of combined modality
therapy
– Radiation+chemo, Bevacizumab, …
•Easier re‐treatment of disease.

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Protons ‐ Disadvantages
•Traditionally, accelerator cost and space
requirements;
•Space requirements reduced with
superconductor magnets;
•New approaches to proton acceleration:
Dielectric Wall Accelerator and high power
lasers could bring the costs down.

Protons ‐ Radiobiology
•Radiobiologic properties of protons are
unremarkable.
•RBE = 1.1, relative to MeV (Co‐60)
photons.
•Average LET 0.5 keV/μm, up to 100
keV/μm, at the end of the range.
• OER ~ 2.5‐3.

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Protons ‐
Medulloblastoma
PHOTON “dose bath”
S
100%

60%
PROTONS

10%

http://gray.mgh.harvard.edu
/

Protons ‐
Nasopharynx
Photons (IMRT) Protons Dose bath

http://gray.mgh.harvard.edu
/

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Protons ‐
Paraspinal
Photons Protons

Dose bath

http://gray.mgh.harvard.edu
/

CSI Medulloblastoma
3yr old male
•2 months history of increasing atoxia,
headaches → nausea & vomiting 4~5/d →
Emergency → MRI revealed mass at 4th
ventricle measured 4.3 x 3.7 x 4.0 cm3
•Post gross total resection
•Grade 4 medulloblastoma
•Proton therapy recommended by his
Radiation Oncologist at Yale University
School of Medicine
•CNS 0331 randomized clinical trial to
compare
– standard vs reduced dose CSI
– Post fossa boost vs reduced boost + tumour bed
•Proton therapy (supine, daily anesthesia,
gantry room~1.5 hr)
– CSI: 1.8 Gy x 10
– Post fossa boost: 1.8 Gy x 3
– Tumour bed boost: 1.8 Gy x 17

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CSI Medulloblastoma (cont’d)

Carbon Ions

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A 670-ton gantry at the Heidelberg Ion-Beam Therapy Center provides 360° rotation for
carbon-ion beams to be aimed precisely at a patient's tumor. The treatment room (not
visible) is located in the upper left- hand corner. The magnets (orange) used to direct
the beams rotate on an axis perpendicular to the V-shaped stand.

Physics Today, June 2015, 24-25.

Carbon Ion Radiotherapy

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Carbon Ion Radiotherapy

Carbon Ions ‐ Radiobiology

•High LET – low OER: important advantage in
treatment of hypoxic tumours;
•High LET – reduction of repair capacity:
potential disadvantage for sparing normal
tissues;
•Smaller variation in radiation effectiveness
with cell cycle: potential disadvantage for
sparing of normal tissues.

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Carbon Ions ‐ RBE

H. Suit et al. / Radiotherapy and Oncology 95 (2010) 3–22.

Carbon Ions ‐ Fragmentation

Figure 1. A simplified model of the nuclear fragmentation due to peripheral collisions of projectile and
target nucleus as described by Serber [4].

K. Gunzert-Marx et al. / New Journal of Physics 10 (2008) 075003.

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Carbon Ions ‐ Fragmentation

Figure 2. The ionization function (Bragg curve) of a 200MeVu−1 12C ion beam in water. The
measurement was performed with parallel-plate ionization chambers and a precision water absorber
[5, 6]. Calculations with the Monte- Carlo code (particle and heavy ion transport code system
(PHITS)) (see section 4) are in good agreement with the measurement. The lower part with
magnified ordinate scale shows the contribution of fragments with different atomic numbers Z as
calculated with PHITS. The thickness of the water target used in our fragmentation measurements is
indicated by an arrow.

K. Gunzert-Marx et al. / New Journal of Physics 10 (2008) 075003.

Carbon Ions ‐ Fragmentation

Fig. 4. Display of the penetration of fragmentation tails of 195 MeV, 281 MeV and 392 MeV 12C
beams. This contrasts with no tail for proton beams of energies of 103 MeV, 147 MeV and 204 MeV.

H. Suit et al. / Radiotherapy and Oncology 95 (2010) 3–22.

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Carbon Ions – PET Verification

•Positron emitting 11C and 10C are produced
through nuclear fragmentation;
•Positrons emitted during decay annihilate and
produce annihilation photons (511 keV), which
can be detected and visualized in a positron
emission tomography (PET) scanner.

Summary

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OER, RBE and

LET

290
X‐rays 10 MeV MeV
Carbon
(kV‐MV ions
Protons
range)

Hall, Fig 7.10

Summary of Radiobiological
Properties of Radiation
Beams
X‐Rays Fast Protons He Ions C Ions
Neutrons
Pseudo‐ Pseudo‐ Bragg Peak Bragg Peak Bragg Peak
Attenuation exponential exponential
with depth
1 1 1.1 1.4 3
Average RBE

2.5 2.5 2.4 2.3 1.7

Average OER

Integral Dose high highest low lower Lowest

Availability Everywhere none ~100 ~none ~5 centers

centers worldwide
worldwide

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Neutrons ‐ Summary
•Neutrons are indirectly ionizing. In
tissue, they give up their energy to
produce recoil protons, α‐particles, and
heavier nuclear fragments.
•Penetration in tissue similar to MV
photons however radiobiological
properties are different: low OER and
high RBE.
•Small advantage shown for certain
tumours (salivary, sarcoma and prostate),
but at unacceptable levels of normal
tissue damage.

BNCT ‐ Summary
•Principle: tumour seeking drug with
boron + exposure to thermal neutrons.
•Difficulties with developing a suitable
drug.
•Poor tissue penetration by thermal
neutrons.

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Protons ‐ Summary
•Excellent physical dose distributions.
•Biologic properties similar to those of
x‐rays.
•Protons are well established in the
treatment of choroidal melanoma or
tumors close to the spinal cord in which
a sharp cutoff of dose is important.
•Hospital‐based high‐energy cyclotrons
with isocentric mounts are now
becoming more broadly available.

Carbon Ions ‐ Summary

•Experiencing a renaissance in Europe and
Japan.
•Similar to protons the Bragg peak need to
be spread out by varying the energy.
•RBE higher than for protons and variable
with energy.
•Hypofractionation (1‐2 fractions) is under
investigation for carbon ions.
•Possibility of imaging with PET.

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