PROTON THERAPY

IN CLINICAL PRACTICE:
PAST, PRESENT AND FUTURE

Michael Goitein
Harvard Medical School
& Ankerstrasse 1, Windisch 5210
Switzerland

AAPM Symposium, Baltimore, May 2009

Michael Goitein, AAPM Symposium, Baltimore, May 2009 1
 Synopsis
1. Physics
interactions of p
protons with matter
treatment planning
2. Technology
beam generation
generation, shaping and delivery
patient handling
integration
3 Radiobiology
3.
RBE
modelling and treatment strategy
4 Clinical Application
4.
clinical experience
clinical trials

Michael Goitein, AAPM Symposium, Baltimore, May 2009 2

 INTERACTIONS OF PROTONS WITH MATTER

69
When
proton penetration
MeV
primary
ICRU (1993).
(1993) S
Stopping
i PPowers and
d energy 231
changed MeV
Ranges for Protons and Alpha
Particles, ICRU Report 49

multiple Coulomb scattering graph courtesy

of Bernie Gottschalk

Gottschalk et al. ((1993)) Multiple

p
 ~ 2%
Coulomb scattering of 160 MeV of range, R
protons. Nucl Instr Methods Phys
Res B74:467–490. range, R

andd http://huhepl.harvard.edu
htt //h h l h d d Based on a figure courtesy of Eros Pedroni, PSI
/~gottschalk/
nuclear interactions
there is a vast literature

Michael Goitein, AAPM Symposium, Baltimore, May 2009 3

 DOSIMETRY

• See ICRU report number 78

 basically adopts IAEA’s prior protocol (TRS 398)
(thus eliminating a 2% discrepancy)
 proton dosimetry is based on X-ray calibration
off ion chambers, with correction factors
f
 however, the largest correction factor is in
the w-value of protons in the ion chamber gas,
and
d thi
this value
l llargely
l relies
li on CCalorimetric
l i t i
determinations
• Stated standard error of from 2.0% to 2.3%
• Most important point:
 Proton dosimetry is now standardized
and the standard is (or will soon be)
near-universally followed

Michael Goitein, AAPM Symposium, Baltimore, May 2009 4

INHOMOGENEITIES

and

Michael Goitein, AAPM Symposium, Baltimore, May 2009 5

 INFINITE SLAB

Figure based on data of Eros Pedroni

X-rays
X rays

dose protons
range
change

intensity
change

interface effects are minor (few %)

– Koehler (unpublished) depth
Michael Goitein, AAPM Symposium, Baltimore, May 2009 6
 SEMI-INFINITE SLAB (thin edge)

plastic
air Med Phys 5:265 (1978)

scanning diode

overlying
l i
material

Goitein et al., Med Phys 5: 265 (1978) Michael Goitein, AAPM Symposium, Baltimore, May 2009 7
 Q. How wide a sliver
can cause range
g shortening?
g
2mm wide Teflon “sliver”

angular
l ffeathering
th i

Goitein & Sisterson

Radiat Res
Radiat. Res. 1978; 74:217

A: pretty small (~ 1mm)

- at the edge of available imaging and computation resolution!
Michael Goitein, AAPM Symposium, Baltimore, May 2009 8
 DISTAL EDGE DEGRADATION

Human skull pristine

(water-filled) Bragg Peak
in water,
no skull
detector

water tank

in water,
no skull

spread-out
Bragg Peak
Urie et al. Phys Med Biol 1986; 31: 1 Michael Goitein, AAPM Symposium, Baltimore, May 2009 9
 lateral beam passing
through inhomogeneities
 distal dose
degradation
position C; SOBP

“ k up”” beam
“make b
Dose (%) to “fill in” the
distal dose deficit

100
90
80

50

20
0
0 5 10 15
Depth (cm)

Michael Goitein, AAPM Symposium, Baltimore, May 2009 10

 PROTON CONSUMER’S REPORT SCHEMA

past present future

d
done / to
t do
d currentt status
t t

almost nothing as good as it gets

very little
some mostly understood
quite a lot
l
glass half full
really a lot

some work to be done, pretty ignorant

i
but not very critical
Michael Goitein, AAPM Symposium, Baltimore, May 2009 11
 INTERACTION OF PROTONS - SUMMARY

past present future

proton
t penetration
t ti

multiple Coulomb
scattering
nuclear interactions

dosimetry

inhomogeneities
awareness
Michael Goitein, AAPM Symposium, Baltimore, May 2009 12
 TREATMENT PLANNING

• image-based geometric design

• dosimetric design (manual)
• uncertainty
• intensity-modulated proton
therapy (IMPT)
• algorithmic
l ith i plan
l design
d i
- optimization and robustness

Michael Goitein, AAPM Symposium, Baltimore, May 2009 13

 WHAT IS DIFERENT ABOUT TREATMENT PLANNING
FOR PROTON THERAPY?

adapted from
Radiation Oncology:
A physicist
physicist’ss-eye
eye view
view.
Michael Goitein.
Springer, New York, 2007
see also: ICRU report 78 Michael Goitein, AAPM Symposium, Baltimore, May 2009 14
 GEOMETRIC DESIGN – image based

Beam’s-eye view
aperture
p drawingg
virtual simulation

McShan et al. BJR 1979

use off CT
sagittal / coronal
reconstructions
contour definition
f

image registration DRRs

( lti
(multi-modality
d lit imaging
i i reference for
– “hat & head” technique setup film
Chen, Kessler, Pelizzari…)
Michael Goitein, AAPM Symposium, Baltimore, May 2009 15
 DOSIMETRIC DESIGN

• algorithms
broad beam - radiological path length
pencill b
beam e.g. Hong et al. A pencil beam algorithm for proton
dose calculation. Phys Med Biol 41:1305–1330
Monte Carlo 0
10

e g GEANT,
e.g. GEANT 30

purpose-written code 50

70

• dose display 90

color wash (with scale!) 110

side-by-side display
130

dose-difference displays
• plan assessment
and comparison
X-rays

DVHs protons

score functions
Shipley et al. Proton radiation as boost therapy for
localized prostatic carcinoma. JAMA 1979; 241:1912 Michael Goitein, AAPM Symposium, Baltimore, May 2009 16
 UNCERTAINTY

• Virtually all aspects of treatment planning are subject

g
to significant (mainly
( y systematic)
y ) uncertainties,, such as:
 definition of gross tumor, CTV, and normal anatomy
 patient and organ localization and movement
 dose estimation
(Goitein. Calculation of the uncertainty in
 treatment delivery the dose delivered in radiation therapy.
 etc.
t etc.
t Med Phys.
Phys 1985; 12:608-612)
12:608 612)

• It is the job of the plan designer(s) to:

 assess the
h uncertainties
i i (at
( a given
i level
l l off confidence)
fid )
 take steps to minimize them to the extent practically
possible
p
 plan the treatment taking the residual uncertainties
into account
Michael Goitein, AAPM Symposium, Baltimore, May 2009 17
 COMPENSATION FOR MIS-REGISTRATION

idealized compensation but, mis-registration can lead to undershoot:

solution, (if one gives priority to tumor coverage):

solution
“open up” the compensator (at the price of certain overshoot)

Michael Goitein, AAPM Symposium, Baltimore, May 2009 18

 COMPENSATION FOR MULTIPLE SCATTERING

At 15cm depth, ≃ 3mm

 ~ 2%
of range, R

range, R

Based on a figure courtesy of Eros Pedroni, PSI

unwanted
undershoot

Michael Goitein, AAPM Symposium, Baltimore, May 2009 19

 COMPENSATION FOR MULTIPLE SCATTERING

At 15cm depth, ≃ 3mm

 ~ 2%
of range, R
so, expand compensator
range, R

Based on a figure courtesy of Eros Pedroni, PSI

Michael Goitein, AAPM Symposium, Baltimore, May 2009 20

 COMPENSATOR DESIGN (physical and virtual)

compensates for mis-registration

and multiple scattering
Urie M et al. (1984) Compensating for heterogeneities
in proton radiation therapy. Phys Med Biol 29:553–566
Michael Goitein, AAPM Symposium, Baltimore, May 2009 21
 COMPENSATING FOR REGISTRATION ERROR
– simple
p inhomogeneity
g y

simple (nominal) bolus “expanded” bolus

correct alignment 3 mm misaligned

Urie M et al. (1984) Compensating for heterogeneities in proton
radiation therapy. Phys Med Biol 29:553–566 Michael Goitein, AAPM Symposium, Baltimore, May 2009 22
 COMPENSATING FOR REGISTRATION ERROR
– complex
p inhomogeneities
g

simple (nominal) bolus “expanded” (by 3mm) bolus

correct alignment 3 mm misaligned

Urie M et al. (1984) Compensating for heterogeneities in proton
radiation therapy. Phys Med Biol 29:553–566 Michael Goitein, AAPM Symposium, Baltimore, May 2009 23
 BEAM DIRECTION NEAR-TANGENT TO A SKIN:TISSUE INTERFACE

• The greatest inhomogeneity is that which exists at the

interface between the patient and the surrounding air
• iff the
h beam
b direction
d is near-tangent to a skin:tissue
k
interface, the dose distribution can be very sensitive to
patient motion or misalignment

translation rotation
Michael Goitein, AAPM Symposium, Baltimore, May 2009 24
 CALCULATION & DISPLAY
OF UNCERTAINTY
• Compute 3 dose distributions
nominal dose at a pixel computed using
nominal values of all variables
lower bound dose at a pixel computed using the value of each variable
that would tend to yield the lowest dose
(but use the computed “upper bound” value, if lower)

upper bound
b d dose at a pixel computed using the value of each variable
that would tend to yield the highest dose
(but use the computed “lower bound” value, if higher)

Michael Goitein, AAPM Symposium, Baltimore, May 2009 25

 A MAJOR CONSEQUENCE OF UNCERTAINTY

• larger-than-desired safety margins

Michael Goitein, AAPM Symposium, Baltimore, May 2009 26

 GEOMETRIC DESIGN, DOSE CALCULATION & UNCERTAINTY

• image-based geometric past present future

design
use of imaging

image
g registration
g

time variations (4D)

• dosimetric design (manual)

broad- & pencil-beams

Monte Carlo

• uncertainty
computation, and allowance
for the uncertainties
Michael Goitein, AAPM Symposium, Baltimore, May 2009 27
 TREATMENT PLANNING

• image-based geometric design

• dosimetric design (manual)
• uncertainty
• intensity-modulated proton
therapy (IMPT)
• algorithmic
l ith i plan
l design
d i
- optimization and robustness

Michael Goitein, AAPM Symposium, Baltimore, May 2009 28

 OPTIMIZATION

• Why is the subject of optimization important?

1. In IMPT, which presently requires pencil-beam scanning, there are
so many variables that one needs a computer algorithm to set them
perhaps 10,000 pencil beams or more, times the 3 variables of
intensity, depth of penetration and transverse size for each pencil beam
2 Even in uniform
2. uniform-beam
beam irradiation,
irradiation the choice of penetration (which can
vary over the field, is difficult and can benefit from computer-based
solutions (e.g. field-patching)
• Optimization requires a search algorithm to find the optimal set of
variables, and a score function. Generally:
a solution to the search problem is not hard to find, though it may be
computationally demanding
a clinically
li i ll meaningful
i f l score function
f ti iis extremely
t l diffi
difficult
lt to
t fi
find
d
• In proton therapy, however
due to the almost two orders of magnitude more variables, the search
problem becomes even more demanding
the score function is further complicated due to uncertainties in the
penetration of each pencil beam
Michael Goitein, AAPM Symposium, Baltimore, May 2009 29
 ROBUST OPTIMIZATION

• One simply has to deal with uncertainties.

• A robust plan is one which is not too negatively affected
b th
by the unavoidable
id bl or iirreducible
d ibl uncertainties.
t i ti
• There are two ways of achieving robustness:
 find the p
plan which has the least-bad
“worst case”
the worst case is the (unphysical) dose
distribution for which, for a given level
of uncertainty in the treatment variables
in each voxel within the PTV the dose is A Lomax, PSI
set to the lowest possible dose; and see, also: Shalev et al. Treatment
in each voxel within an OAR the dose is planning using images of regret.
set to the highest possible dose. M dD
Med Dosim.
0
i 1988
1988;13(2):57-61.
13(2) 57 61

 find the plan which on average has the best score

– when averaging over all sources of uncertainty
Unkelbach J and Oelfke U Phys. Med. Biol. 49 (2004) 4005–29 these approaches have
Unkelbach et al. Accounting for range uncertainties... demonstrated very
promising results
Phys. Med. Biol. 52 (2007) 2755–2773 Michael Goitein, AAPM Symposium, Baltimore, May 2009 30
 IMPT, OPTIMIZATION AND ROBUSTNESS

past present future

• IMPT
understanding
d t di off th
the problem
bl

development of solutions

• OPTIMIZATION

search
h techniques
h i

dose-based optimization

biological optimization

• ROBUST PLANNING
Michael Goitein, AAPM Symposium, Baltimore, May 2009 31
 Synopsis
1. Physics
interactions of p
protons with matter
treatment planning
2. Technology
beam generation
generation, shaping and delivery
patient handling
integration
3 Radiobiology
3.
RBE
modelling and treatment strategy
4 Clinical Application
4.
clinical experience
clinical trials

Michael Goitein, AAPM Symposium, Baltimore, May 2009 32

 GENERAL STATUS OF THE TECHNOLGY OF PROTON THERAPY

• There is a misapprehension that, since proton therapy has

been developed over about half a century, the technology
is mature.
• It is not.
g y because:
• This is largely
the early experience was in research environments in which
less-than-efficient procedures were tolerated
the current commercial offerings
g largely
g y copied
p the existing
g
technologies (with the addition of gantries)
IMPT is a very recently-recognized possibility and has not had
time to be satisfactorily commercially developed
• But, don’t be too alarmed, because:
proton therapy is currently being delivered with the existing
technology to the benefit of large numbers of patients
the developments are needed to allow protons to reach their full
potential, and to be used in a clinically streamlined fashion.

Michael Goitein, AAPM Symposium, Baltimore, May 2009 33

 BEAM GENERATION

• The technology of currently-used proton accelerators

is prett
pretty well
ell de
developed
eloped
synchrotrons both are adequate and reasonably
cyclotrons reliable – except that:

• There is still an intensity problem - reflected in:

low beam intensity at low energies (cyclotrons)
too large pencil beam sizes (caused also by other factors)

• Cost remains a factor (we’re still waiting for true

marketplace competition 15 years after MGH signed
the first commercial contract for a proton facility)

Michael Goitein, AAPM Symposium, Baltimore, May 2009 34

NEW TECHNOLOGIES FOR PROTON GENERATION

• Good luck

• but, beware!
remember
b ththe fate
f t off d-T
d T generators
t iin
neutron therapy

• and,
and don
don’tt compromise performance – e.g.
eg
lowering the maximum energy
failure to support IMPT
etc.
etc

Michael Goitein, AAPM Symposium, Baltimore, May 2009 35

 BEAM SHAPING: SCATTERED BEAMS

• The technology has been very fully developed

primarily by Andy Koehler, Bernie Gottschalk, and colleagues at
the Harvard Cyclotron Laboratory
• Current commercial systems
y p
primarily
y use the “historic”
technology, including double-scattering - with a few
enhancements, e.g.
automatically
y selectable range
g modulator wheels
beam gating to vary the depth of the SOBP

• The depth characteristics are fairly satisfactory, using the

currentt range modulator
d l t ttechnology
h l
except for low energies for which the Bragg peaks are too
narrow to stack easily and a better method of spreading
them (e.g.
(e g ridge filters) is needed

Michael Goitein, AAPM Symposium, Baltimore, May 2009 36

 BEAM SHAPING: SCATTERED BEAM PENUMBRA

• But, beam penumbra in the current scattered beam implementations

is very inadequate (worse than Cobalt-60
Cobalt 60 in many cases)
• For scattered beams, the historically achieved penumbrae were
OK due to their long throw, but in the current gantry
implementations the penumbra is far from satisfactory.
satisfactory
This is because they
use double-scattering range compensator

with
ith a relati
relatively
el short
modulator full dose
region

throw (SAD) first second

scatterer
scatterer

protons

large effective
source size (a few cm)
patient
scattered
d bbeam technology
h l compensated
range modulator
tumor (i.e. target
volume)
aperture

Michael Goitein, AAPM Symposium, Baltimore, May 2009 37

 BEAM SHAPING: SCANNED BEAMS
and intensity-modulated
y proton therapy
p py ((IMPT))

• IMPT requires the use of a pencil beam of protons whose

Bragg peak is scanned throughout the target volume
while its energy (penetration) and intensity are varied at
will.

gantry
“nozzle” - control
can rotate
t t system
around
patient
scanning
magnets

Michael Goitein, AAPM Symposium, Baltimore, May 2009 38

 BEAM SHAPING: SCANNED BEAMS
and intensity-modulated
y proton therapy
p py ((IMPT))

• IMPT requires the use of a pencil beam of protons whose

Bragg peak is scanned throughout the target volume while its
energy (penetration)
( t ti ) andd iintensity
t it are varied.
i d
• The only significant experience with IMPT
to date has been at the Paul Scherrer
Institute (PSI) in Switzerland where they
developed, and have used since 1996, a
prototype so-called spot-scanning gantry
• PSI are now building a second gantry
featuring isocentric rotation and faster
scanning (due to start treating in 2010)
• Commercial scanning systems are
just now in their infancy.
IMPT technology

Michael Goitein, AAPM Symposium, Baltimore, May 2009 39

 BEAM SHAPING: SCANNED BEAM PENUMBRA

• In scanned beams, the beam penumbra is set by the

diameter of the pencil beam near the end of range.
• This has two components:
scattering in the patient
about which technology can do nothing
pencil beam size in the absence of the patient
which is entirely due to the technology

• If one wants to at least match, at a depth of 10cm, typical

linac penumbrae of about 7mm (80-20%), the pencil beam
size at isocenter in the absence of the patient (i.e. due to
the technology) needs to be no more than about:
 ≈ 3.5 mm – i.e. a fwhm of no more than ≈ 8 mm

• Current implementations fall short of this important goal.

goal

Michael Goitein, AAPM Symposium, Baltimore, May 2009 40

 INTERPLAY EFFECT

• The main downside of beam scanning is that, if there

is motion of the patient and/or the tumor, so-called interplay
effects
ff t can lead
l d tot up-and-down
d d d
dose variations
i ti within
ithi th
the ttargett
(dose mottle).
Phillips M et al. Effects of respiratory motion on dose uniformity with a
charged particle scanning method. Phys Med Biol. 1992 Jan;37(1):223-34
Bortfeld T et al. Effects of intra–fraction motion on IMRT dose delivery…
Phys Med Biol 47:2203–2220.

scan scan Dose mottle is not just

scan cell
ll cell
ll theoretical It has been
theoretical.
observed at about the
14% (SD) level in an
animal experiment
at PSI,, caused merely
y
by ~2mm movements
of the mouse intestine
irradiated in a scanned
10 mm pencil beam!
Gueulette
G l et al.
l IJROBP
cell has received cell has received 2005;62:838-845
~5 times intended dose ~0 times intended dose
Michael Goitein, AAPM Symposium, Baltimore, May 2009 41
 CURRENT SOLUTION(S) TO THE INTERPLAY PROBLEM

• First, reduce the amount of motion to the extent possible

 respiratory gating
 abdominal compression
 tumor tracking
• Then, repaint the field many times. But…

static 1 scan 2 scans 3 scans 5 scans 10 scans

Grözinger et al. Simulations to design an online motion compensation
system for scanned particle beams Phys.
Phys Med.
Med Biol.
Biol 51 (2006) 3517
3517–3531
3531
and thesis: http://elib.tu-darmstadt.de/diss/000407/
Michael Goitein, AAPM Symposium, Baltimore, May 2009 42
 BEAM SHAPING

• In depth
scattered beams

scanned beams

• Laterally
ll ((penumbra)
b )
scattered beams

scanned beams

30
Michael Goitein, AAPM Symposium, Baltimore, May 2009 43
 IMMOBILIZATION AND MOTION MANAGEMENT

• Proton therapy has, from its very beginning,

emphasized accuracy of beam placement (relative to
the target volume) and tight margins where possible
and indicated.
• This is for two reasons:
compensators need to be in accurate registration with
the inhomogeneities and beam shapes they are
intended to compensate for in order to avoid an
unintended distribution of dose
a main goal of proton therapy is to minimize the
volume of normal tissue outside the target volume
which receives a high dose
• This has resulted in a number of developments which
have found wide application
Michael Goitein, AAPM Symposium, Baltimore, May 2009 44
 PLANNING, IMMOBILIZATION AND LOCALIZATION

patient #1 at HCL (1974)

planning based on radiographs

patient #2 at HCL (1974)

planning based on smearing tomography alignment

Michael Goitein, AAPMbased on radiographs
Symposium, Baltimore, May 2009 45
 IMMOBILIZATION AND LOCALIZATION (contd.)

Verhey et al. Precise positioning of patients for radiation therapy.

Int J Radiat Oncol Biol Phys. 1982; 8:289-294
Michael Goitein, AAPM Symposium, Baltimore, May 2009 46
 GATING & TARGET TRACKING (intra- & inter- fraction)

respiratory gating (NIRS, Japan)

implanted
gold seeds

rectal probe
& water-
filled balloon

Shipley et al. Proton radiation as boost therapy for Minohara et al. Respiratory gated irradiation
localized prostatic carcinoma. JAMA 1979; 241:1912 system for heavy-ion radiotherapy. Int J Radiat
Oncol Biol Phys 47(4):1097–1103;2000

PSI high-mag.
h h image
of anterior eye
ocular tumor tracking with the position
though real time video of the pupil being
tracking of anterior outlined.
eye position (HCL, PSI)

picture courtesy J Vervey, PSI

Michael Goitein, AAPM Symposium, Baltimore, May 2009 47
 PATIENT SUPPORT ASSEMBLY

HCL 6-degree
of freedom patient
supporter (Wagner)

Commercial
i l 6 degree
d
of freedom patient
couch (IBA)

Orsay-Curie
O C i
6 degree of freedom
patient couch
(Mazal) The additional
degrees of
freedom are
required to
adjust for small
rotational
misalignments
of the patient.
Michael Goitein, AAPM Symposium, Baltimore, May 2009 48
 THROUGHPUT

• Currently it generally takes too long, and is too hard, to set

up and treat a patient.
this is hard on the patient tends to reduce
accuracy
this is hard on the staff
it can degrade quality, and it
reduces throughput and hence
increases costs
• One partial solution is to perform
the patient setup outside the
treatment room and bring him or
her into the treatment room when
i b
it becomes available
il bl without,
ih iin
principle, the need for further
localization, à la PSI.
• But, this does not get at the root of the problem which is:
inadequate systems engineering – and inadequate
specification of the needs Michael Goitein, AAPM Symposium, Baltimore, May 2009 49
 INTEGRATION

• Integration and Workflow

are concepts which are
more talked about than
put into practice.

Michael Goitein, AAPM Symposium, Baltimore, May 2009 50

 PATIENT HANDLING AND INTEGRATION

• patient handling
immobilization and
motion management

patient support
assembly

throughput

• integration
workflow

40
Michael Goitein, AAPM Symposium, Baltimore, May 2009 51
 Synopsis
1. Physics
interactions of p
protons with matter
treatment planning
2. Technology
beam generation
generation, shaping and delivery
patient handling
integration
3 Radiobiology
3.
RBE
modelling and treatment strategy
4 Clinical Application
4.
clinical experience
clinical trials

Michael Goitein, AAPM Symposium, Baltimore, May 2009 52

 RBE = 1.10 isn’t all that bad...

1.22

1.10

Paganetti et al. 2

IJORB 53: 407 (2002)

Michael Goitein, AAPM Symposium, Baltimore, May 2009 53
 DOSE

100%
bio-effective dose
physical dose

DEPTH
Michael Goitein, AAPM Symposium, Baltimore, May 2009 54
 But, proton RBE needs (some) refinement

RBE

1.0
RBE rises across SOBP
1 3 ?? order of 1% / cm
DOSE
2 4 “blip” near
100% end of SOBP
? 5 - 10%
bio-effective dose
physical dose RBE  1.10 in 5
center of SOBP
elongation
g of
RBE in entrance region a bit less range ~ 1-2 mm.
(? 5%) than at SOBP center?

6 RBE depends on dose per fraction

7 RBE depends on tissue type & endpoint
DEPTH
Michael Goitein, AAPM Symposium, Baltimore, May 2009 55
 MODELLING AND TREATMENT STRATEGY

reduced
d d tumor
dose in the
region in which
the tumor is
close to the
brainstem increased
brainstem dose
accepted in the
small region in
which it is close
to the tumor

Michael Goitein, AAPM Symposium, Baltimore, May 2009 56

 MODELLING TUMOR CONTROL PROBABILITY (TCP)

The development of
p y
biophysical models
suggested that, for example,
a partial boost to a tumor
may increase the TCP

50% volume
partial
minimum boost 35 80% volume
dose dose 90% volume
TCP 30
increase 100% volume
(%) 25
 =2
 50
20
boost 15
dose
10
5

ttargett distance 0
0 5 10 15 20
volume Boost Dose (%)
Goitein et al. Proceedings of the 19th LH Gray
Conference (Brit. J. Radiol.). 1997: 25-39 Michael Goitein, AAPM Symposium, Baltimore, May 2009 57
 BUT (as seen in IMRT and with interplay effects)…
BEWARE DOSE MOTTLE!

dose dose mottle

average dose

amplitude
p

target volume distance

TCP (actual dose distribution < TCP (average tumor dose)

for a dose mottle of ±7.5% TCP ≈ - 4 %
for a dose mottle of ±10% TCP ≈ - 6.5 65%
Brahme A. Acta Radiol Oncol
23: 379-391 (1984) Michael Goitein, AAPM Symposium, Baltimore, May 2009 58
 MODELLING NORMAL TISSUE
COMPLICATION PROBABILITY (NTCP)
serial structure parallel structure
radiattion

on
radiatio
0.6 0.6

0.5 a = 10 0.5 a=2

1.0
0.4 0.4
NTCP

0.3 0.9 0.3

0.2 0.2 1.0
0.8
09
0.9
0.1 0.1 0.8
0.7
0 0 0.7
0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8
relative volume relative volume

Modelling supported the idea that organs could tolerate a

higher dose if it was only delivered to part of the organ.
Michael Goitein, AAPM Symposium, Baltimore, May 2009 59
 RADIOBIOLOGY: dose-volume effects

• There are many important but unanswered questions

the answers to which are relevant for all radiations, but particularly to particles with which
one is attempting to spare normal tissues particularly effectively
• Some of the unsolved issues are:
“bath-or-shower dilemma” (is it better to deliver
a lower dose to a larger volume of normal vs.
tissue, or a higher dose to a smaller volume?)

how does functional damage to an organ or tissue dose, d, to

depend on the relative (or absolute) volume a relative
volume, v
irradiated to high dose?

how does functional damage to an organ or tissue

depend on the (lower) dose delivered to the rest lower dose,
d’, to rest
of the volume? of volume

how does the radiation damage of an organ or tissue

depend on the radiation experience of nearby dose, d’’, to
tissues and organs? surrounding
volume
• We need to resurrect whole-organ and whole-organism radiobiology
• When we know the answers to some of these questions, we will need
new biophysical models so we can use computers to optimize treatments
Michael Goitein, AAPM Symposium, Baltimore, May 2009 60
 RBE, MODELLING AND TREATMENT STRATEGY

• RBE

• Radiation response
of tissues
data

modelling

treatment strategies

Michael Goitein, AAPM Symposium, Baltimore, May 2009 61

 Synopsis
1. Physics
interactions of p
protons with matter
treatment planning
2. Technology
beam generation
generation, shaping and delivery
patient handling
integration
3 Radiobiology
3.
RBE
modelling and treatment strategy
4 Clinical Application
4.
clinical experience
clinical trials

Michael Goitein, AAPM Symposium, Baltimore, May 2009 62

 CLINICAL EXPERIENCE

• Some 61,000 patients have been treated with proton

beam therapy as of Feb
Feb. 2009
2009.
• The largest single group is comprised of ~17,000
patients with ocular melanomas.
p
http://ptcog.web.psi.ch/patient_statistics.html

• There have been only a limited number of clinical trials

off proton beam
b therapy,
h andd only
l two randomized
d d
clinical trials of protons vs. conventional radiotherapy.
• The experience to date should perhaps be read as a
confirmation that the theoretical arguments for proton
beam therapy have been upheld in the limited number
off situations in which
h h they
h have
h been
b tested.
d
Goitein & Goitein. Swedish protons. Acta Oncol. 2005;44(8):793-7
Michael Goitein, AAPM Symposium, Baltimore, May 2009 63
 Chondrosarcoma
- local
l l control
t l

Choroidal melanoma 08
0.8

Local Control
0.6
- local control 0.4

0.2

0
0 5 10 15
Time (years)

100

Paranasal sinus tumors

80

33 squamous cell carcinomas,

Percent (%)
60
30 carcinomas with neuroendocrine
differentiation 40

20 adenoid cystic carcinomas 20

local control
Local control
regional control
13 soft tissue sarcomas, and Regional control
Freedom from
freedom distant
from metastasis
distant metastases
6 adenocarcinomas. 0
0 1 2 3 4 5 6 7 8
The median dose was 71.6 CGE. Michael Goitein, AAPM Symposium,
Follow-UpBaltimore,
Time (years) May 2009 64
 THE RATIONALE FOR JUDGING THE CLINICAL
SUPERIORITY OF PROTONS VIS-À-VIS
VIS À VIS X-RAYS
X RAYS

 For the same dose to the target volume, protons deliver a

l
lower physical
h i l dose
d to the
h uninvolved
i l d normall tissues
i than
h
do high-energy X-rays.
 There is veryy little difference in tissue response
p p
per unit
dose between protons of therapeutic energies as
compared with high-energy X-rays, so that the only
relevant
ee a td differences
e e ces a are
epphysical.
ys ca
 There is no medical reason to irradiate any tissue judged
not to contain malignant cells.
 Radiation damages normal tissues and the severity of that
damage increases with increasing dose.
Suit H, et al. Should positive phase III clinical trial data be required before proton
beam therapy is more widely adopted? No. Oncol 2008;86:148153
No Radiother Oncol.

Each of these 4 statements is established experimentally

beyond reasonable doubt Michael Goitein, AAPM Symposium, Baltimore, May 2009 65
 RANDOMIZED CLINICAL TRIALS

• There are two fundamental principles which govern whether

a randomized clinical trial (RCT) is ethically appropriate:
The arms of the study must be in equipoise. That is to
say, the arms must be judged to be substantially
equivalent from a patient’s
patient s point of view
view.
When a doctor agrees to take care of a patient, he or she
is entering into an unwritten contract with the patient to
use his or her best efforts and judgment on behalf of that
patient. There can be no unspoken reservation that
societal interests may take priority over those of the
patient, and the patient may expect to be fully informed
regarding any facts that he or she might deem relevant.
These principles
principles, together with the previous 4 statements,
statements mean that
many otherwise desirable RCTs can not be performed for ethical
reasons - equipoise can not truthfully be said to obtain for them.
Michael Goitein, AAPM Symposium, Baltimore, May 2009 66
 CLINICAL TRIALS (contd.)

• It is a great pity that almost no case-controlled

clinical
l l studies
d h
have bbeen planned
l d or performed.
f d
• It would seem that, in the absence of an ability
in many cases to conduct randomized clinical
trials, carefully designed prospective case-
controlled comparisons between proton centers
and institutions lacking a proton capacity would
be desirable.
• clinical trials
randomized

case-controlled
t ll d

Michael Goitein, AAPM Symposium, Baltimore, May 2009 67

 RECENT TEXTS

• Gottschalk B (2004) “Passive Beam Spreading in Proton Radiation

Therap ” http://huhepl.harvard.edu/~gottschalk/
Therapy” http //h hepl har ard ed / gottschalk/
File named “pbs.pdf” can be extracted from BGdocs.zip
See, also, PowerPoint lectures in BGtalks.zip

• ICRU report 78 “Prescribing, Recording and Reporting

Proton Beam Therapy” Oxford U. Press. Journal of the
ICRU 7(2); 2007

• T.F. Delaney and H.M. Kooy (eds)

“Proton and Charged Particle
Radiotherapy” Lippincott Williams
Radiotherapy
and Wilkins, 2007

• M. Goitein “Radiation Oncology:

A Physicist’s-Eye View” Springer, 2007

Michael Goitein, AAPM Symposium, Baltimore, May 2009 68

 TECHNOLOGY

SUMMARY changes with time current sources

throughput,
of protons
g
integration &
workflow
broad- & pencil- future sources
beam algorithms of protons
INTERACTIONS OF PROTONS RADIOBIOLOGY
Monte Carlo dose scattered beam
calculation technology RBE value(s)
proton
penetration uncertainties:
calcn. and scanned beam
Coulomb allowance for technology tissue response:
scattering & IMPT data
IMPT: scattered beam:
nuclear understanding depth tissue response:
interactions characteristics models
IMPT: scanned beam: treatment
solutions depth strategies based
dosimetry characteristics on biology
optimization: scattered beam:
inhomog- search techniques lateral penumbra
-eneities
CLINICAL TRIALS
optimization: scanned beam:
TREATMENT PLANNING dose-based lateral penumbra randomized
protons vs. X-rays
use of imaging immobilization
optimization: & motion case-controlled
biology-based management protons vs. X-rays
image robust patient support
registration optimization systems

Michael Goitein, AAPM Symposium, Baltimore, May 2009 69

 CONCLUSIONS

• Much has been done.

• Much remains to be done.
• It is important that what has been learned in
the ppast be incorporated
p into the clinical work
of the future - and not simply regarded as
being of purely historical interest and hardly
worth learning about.
about

Michael Goitein, AAPM Symposium, Baltimore, May 2009 70

finis

Michael Goitein, AAPM Symposium, Baltimore, May 2009 71