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Theragnostic imaging for radiation oncology: dose-painting
by numbers
Lancet Oncol 2005; 6: 112–17
University of Wisconsin Medical
School, Department of Human
Oncology, K4/316 Clinical
Sciences Center, WI, USA
(Prof S M Bentzen DSc)
Correspondence to:
Prof Søren Bentzen, University of
Wisconsin Medical School,
Department of Human
Oncology, K4/316 Clinical
Sciences Center, 600 Highland
Avenue, Madison, WI 53792,
USA
[email protected]
See page 66 for a Reflection and
Reaction article on treatmentplanning approaches in radiation
oncology
Søren M Bentzen
Theragnostic imaging for radiation oncology is the use of molecular and functional imaging to prescribe the distribution
of radiation in four dimensions—the three dimensions of space plus time—of radiotherapy alone or combined with
other treatment modalities in an individual patient. Several new imaging targets for positron-emission tomography,
single-photon-emission CT, and magnetic resonance spectroscopy allow variations in microenvironmental or cellular
phenotypes that modulate the effect of radiation to be mapped in three dimensions. Dose-painting by numbers is a
strategy by which the dose distribution delivered by inverse planned intensity-modulated radiotherapy is prescribed in
four dimensions. This approach will revolutionise the way that radiotherapy is prescribed and planned and, at least in
theory, will improve the therapeutic outcome in terms of local tumour control and side-effects to unaffected tissue.
Diagnostic imaging, from radiographs to CT, has been
used throughout the history of radiotherapy to define the
site to which the radiation should be delivered for
patients with cancer. Theragnostic imaging is a method
by which the radiation dose can be delivered in the four
dimensions of space and time to achieve the optimum
outcome after radiotherapy.
What does theragnostic imaging mean? From the
Greek words therapeia (to treat medically) and gnosis
Beam 1
5
10
20
25
30
35
40
(knowledge) theragnostic imaging refers to the use of
information from medical images to determine how to
treat individual patients. Rapid technological and
scientific progress in molecular and functional imaging,
in radiotherapy planning and delivery, and in clinical
radiation biology is making radiotherapy guided by
theragnostic imaging a realistic goal.
Molecular imaging is providing new research
opportunities in the preclinical and clinical development
of new therapies and in the study of small-animal
models of human disease.1,2 To take full advantage of the
curative potential of modern, high-precision radiotherapy, high-quality imaging is needed for
identification of target volumes. Conversely, optimum
use of the spatial information provided by molecular
imaging requires radiotherapy; radiation is a therapeutic
agent that can be modulated in the four dimensions of
space and time, and the dose can be precisely defined to
produce a specified local effect of a given magnitude.
This review explores the latter perspective.
45
Intensity-modulated radiotherapy (IMRT)
50
55
60
Courtesy of C Grau, Aarhus University Hospital, Aarhus, Denmark
65
70 Beam 5
75
Beam 2
80
85
Beam 4
Beam 3
50 mm
Figure 1: IMRT plan for a patient with oropharyngeal cancer
The overlay-colour scale indicates the physically absorbed dose (Gy) of radiation from the whole treatment course.
Five non-uniform treatment fields are used. Note the concavity in the high-dose volume, sparing the dose to the
spinal cord (located at the intersection point of the five beam axes). This feature allows the risk of radiation
myelopathy to be kept very low (<0·1%). Note also the sparing of the left parotid gland, lowering the risk of clinical
xerostomia after radiotherapy.
112
One of the key features underpinning this research is
the theoretical and technological development of IMRT
and inverse treatment planning (figure 1).3 IMRT is the
administration of non-uniform intensities of radiation
(or photon fluence profiles) to patients as a way to create
a specified, non-uniform absorbed dose distribution.
This approach has become feasible as a result of the
increased computer control of linear accelerators used
for radiotherapy during the past few decades, in
combination with the introduction and refinement of
the multileaf collimator—a computer-controlled device,
typically consisting of 20 or more thin collimator plates.
The multileaf collimator is used to create irregularly
shaped fields that conform to the target volume and
modulate the radiation-beam intensity.
Traditionally, radiotherapy dose plans have been
forward planned—ie, a small number of radiation-beam
portals are selected on the basis of the location of the
target volume and any healthy structures that need to be
avoided. Each beam is assigned a weight that determines
http://oncology.thelancet.com Vol 6 February 2005
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its relative contribution to the total absorbed dose. A
computer program, commonly operating on a set of CT
images covering the anatomical region irradiated, is
then used to calculate the dose distribution, and the
irradiated dose from each beam is then normalised to
achieve the prescribed dose in the target volume. Inverse
treatment planning, by contrast, takes a prescribed dose
distribution as the starting point and uses a mathematical optimisation algorithm to identify a set of beam
intensities that approximates the prescribed dose distribution as closely as possible. Typically, the dose
distribution is specified as a desired homogeneous dose
in the clinical target volume plus several dose-volume
constraints for the dose delivered to crucial healthy
structures or organs at risk in the surrounding volume
of healthy tissue.
IMRT and inverse treatment planning have provided
new methods to deliver non-uniform or shaped dose
distributions that are almost impossible to deliver with
conventional static radiation beams. Exploration of the
therapeutic potential of non-uniform dose distributions
is a challenge for preclinical and clinical radiation
research.
Theragnostic imaging for radiation oncology
Theragnostic imaging for radiation oncology aims to
map in three dimensions the distribution of a tumour,
tissue, or functional feature, and to provide information
about the clinical response of tumours or healthy tissues
to radiotherapy. In solid tumours, the aim is to provide
images of phenotypic or microenvironmental characteristics known to affect the clinical response. Most
research has been based on imaging techniques that use
radionuclide-labelled
compounds:
single-photonemission CT (SPECT) or positron-emission tomography
(PET). However, dynamic contrast-enhanced magnetic
resonance (MR) imaging and spectroscopy also have
much potential. Research has also focused on
radiobiological mechanisms that affect—or are
suspected to affect—the outcome after radiotherapy and
for which an appropriate imaging surrogate exists.
Tumour burden and clonogen density
At the most fundamental level, molecular imaging has
the potential to define the real target volume—the
volume consisting of malignant cells that need
irradiation to a therapeutic dose to control the disease.4
One example is the use of proton MR spectroscopy to
discriminate between benign prostate hyperplasia and
malignant tissue,5 and the application of this information
in the planning of conformal transperineal implantation
of therapeutic iodine-125 seeds in the prostate.6
PET scanning with 18-fluorodeoxyglucose is
commonly used as a proxy for tumour burden and has
been intensively investigated for staging of various solid
cancers. However, [18F]FDG is a hexokinase substrate
indicative of glucose metabolism and is an indirect
http://oncology.thelancet.com Vol 6 February 2005
probe that reflects the activity of target enzymes rather
than their concentration.2 Bos and colleagues7
investigated the correlation between [18F]FDG activity
(assessed visually on an arbitrary four-point scale by
three observers) and various histopathological and
immunohistochemical markers in breast tumours.7
They concluded that [18F]FDG uptake is a function of: the
microvasculature for delivery of nutrients; SLC2A1
(GLUT1) for transport of [18F]FDG into cells; hexokinase
for entry of [18F]FDG into glycolysis; and the number of
tumour cells in the volume, the proliferation rate,
number of lymphocytes, and hypoxia-inducible factor 1
(HIF1) for upregulation of SLC2A1.
Tumour hypoxia
Low partial oxygen pressure in human tumours as
measured with polarographic microelectrodes is
associated with poor outcome in patients receiving
radiotherapy.8 Although tumour hypoxia is associated
with malignant progression and a poor prognosis after
other treatment modalities as well as after radiotherapy,9
the idea that hypoxic regions in solid tumours constitute
a resistance problem for radiotherapy seems reasonable.
One strategy to resolve this problem is to boost the
radiation dose to hypoxic regions of the tumour,
provided that these regions can be imaged in three
dimensions. Several radionuclide-labelled compounds
have shown preferential uptake or long-lasting retention
in hypoxic tumour regions in clinical and preclinical
studies. One class of these agents is compounds that
contain a 2-nitroimidazole group (eg, fluoride-18misonidazole, iodide-123-iodoazomycin arabinoside,
and D-125I-iodoazomycin galactopyranoside. Another
class of compounds includes copper-62-labelled diacetylbis(N(4)-methylthiosemicarba-zone) and technetium99m-labelled
4,9-diaza-3,3,10,10-tetramethyldodecan2,11-dione dioxime. The mechanism of action of these
agents is not completely understood, but they seem to be
bioreducible compounds retained in regions with
hypoxic cells with intact mitochondria. One difficulty
with all of these agents is that the signal-to-background
ratio is poor. The search for better markers continues.10
Dynamic contrast-enhanced MR imaging visualises
differences between tissues in the behaviour of a
gadolinium-based contrast medium.11 One example of
this technique is BOLD (blood-oxygen-level dependent)
imaging, which is being investigated as an indirect
method for mapping of hypoxic regions in tumours.12
Work in progress has shown a significant correlation
between pimonidazole immunostaining of coregistered
histological sections and the value of R2*, a relaxation
rate that is sensitive to deoxyhaemoglobin concentration,
derived from BOLD.
Hypoxia causes activation of several cellular response
pathways,9 and one of the most important of these is
regulated by HIF1. Collaborative work by Harris’s
group at Oxford University and our group at the Gray
113
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Cancer Institute, suggests that the outcome after
definitive radiotherapy in patients with squamous-cell
carcinoma of the head and neck depends on the exact
hypoxic pathways activated in a tumour. If this finding is
correct, hypoxic radioresistance is much more than just
the absence of oxygen. Again, the requirements for
molecular imaging would be changed. Serganova and
colleagues’ study13 on imaging of HIF1 transcriptional
activity in tumours in mice has also shown that it is
feasible to map the activation of a specific pathway by
use of PET.
Tumour proliferation
Several randomised controlled trials14–16 have provided
evidence on the importance of overall treatment time,
especially in squamous-cell carcinoma of the head and
neck, with evidence from other tumour sites being less
strong. This feature has been linked to rapid tumour-cell
proliferation during radiotherapy as a resistance
mechanism in fractionated radiotherapy.16 Thus, there is
a rationale for theragnostic imaging of tumour-cell
proliferation, and research on this topic has focused on
radionuclide-labelled nucleosides or aminoacids as
possible imaging agents.17 Several studies18 have looked
at radiolabelled deoxyuridines, but the signal-to-noise
ratio is poor, owing to the rapid degradation of these
compounds in vivo. This problem was largely solved by
the development and clinical testing of 18F-3-deoxy-3fluorothymidine (FLT). Two clinical studies19,20 found
encouraging correlations between local FLT-specific
uptake values and the Ki-67 labelling index detected in
biopsy samples by immunohistochemistry. Ki-67 is a
protein expressed in all phases of the cell cycle but not in
resting cells; it is therefore used widely to measure cell
proliferation. Despite these encouraging results, a study
in animals21 showed limited incorporation of 18F-FLT
into DNA relative to background and further validation
studies seem warranted.
New imaging targets
Many of the new imaging targets under investigation2 are
of immediate interest for theragnostic imaging for
radiation oncology. Examples are cyclin D (which is
overexpressed in many cases of squamous-cell carcinoma
of the head and neck, for example, for assessment of
tumour-cell proliferation), and mitogen-activated protein
kinase for measurement of activation of the RASsignalling pathway. Epidermal growth factor receptor
(EGFR) is expressed in many tumours of epithelial origin
and is implicated in several processes associated with the
malignant phenotype. Clinical studies22,23 have shown a
relation between EGFR expression and the outcome of
definitive radiotherapy in cancer of the head and neck.
Our work has suggested that EGFR expression is directly
linked to the time factor in radiotherapy, making this an
interesting target for theragnostic imaging.24–26 Regions
with high EGFR expression have a large capacity for
114
accelerated repopulation, and these regions would
probably benefit from accelerated radiotherapy (ie,
delivered in a shorter overall time).
With the current advances in molecular risk profiling
and the search for fingerprints of malignant phenotypes
that are sensitive to a specific type of modified
radiotherapy,27 many new theragnostic imaging targets
are likely to be identified in the coming years.
Functional imaging of crucial healthy tissues
Optimisation of the therapeutic ratio of IMRT must
take into account the dose distribution in healthy tissue
as well as tumours. The dose distribution to healthy
tissues can be determined through placement of
simple constraints on the clinically acceptable maximum dose to an organ at risk or by specification of a
single variable of the dose-volume histogram, such as
the fraction of the total organ volume receiving a dose
that exceeds a threshold value. However, just as with
tumours, the full four-dimensional dose distribution
should ideally be constrained. One interesting idea is to
lower the risk of side-effects by reducing the dose
absorbed in regions of an organ that have special
functional importance. These regions could be
identified by use of functional imaging. Seppenwoolde
and
colleagues28
incorporated
lung-perfusion
information from SPECT directly into the
radiotherapy-plan optimisation for patients with
medically inoperable non-small-cell lung cancer. The
researchers showed that this procedure increased the
relative weights of radiation beams passing through
hypoperfused lung regions and reduced the predicted
risk of side-effects to healthy tissue compared with
conventionally optimised treatment plans.
From dose-painting to dose-painting by
numbers
Dose-painting was the term coined by Ling and
colleagues29 in their review of image-guided
radiotherapy. The idea was to visualise tumour
subvolumes with a potential resistance problem and to
paint some additional dose onto that volume. This
notion was applied in a study by Chao and co-workers,30
who identified regions with pronounced retention of
62
Cu(II)-diacetyl-bis(N(4)-methylthiosemicarba-zone) on
a PET scan of a patient with a squamous-cell carcinoma
of the head and neck. In a planning study, they showed
that 80 Gy could be delivered in 35 fractions to the
hypoxic target volume, with 70 Gy in 35 fractions
delivered to the rest of the clinical target volume. By use
of standard bioeffect modelling31 to adjust for the slightly
higher dose per fraction in the hypoxic target volume,
the biological equivalent dose to this volume is about
82 Gy in 2 Gy per fraction. The researchers used dosevolume histograms to show that this dose distribution
could be planned and delivered by means of inverseplanned IMRT.
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Dosimetric features of IMRT delivery
Although a review of the advantages and drawbacks of
IMRT compared with conventional radiotherapy is
beyond the scope of this report, a brief summary of
some of these from the viewpoint of dose-painting by
numbers is relevant. Three-dimensional conformal
radiotherapy (3D-CRT) is a broad class of radiotherapy
techniques that aim to improve the match between the
clinical target volume and the volume irradiated to a
high radiation dose. This aim is achieved without
intensity modulation by use of a limited number of
static beams. 3D-CRT plans typically reduce the volume
of healthy tissue that receives a high dose, while
increasing the dose to the clinical target volume.
The two most frequently aired arguments against
IMRT are that this method of planning and delivery
makes quality assurance very difficult and that there
might be an increased risk of radiation-induced
secondary cancers. Certainly, quality assurance is much
more demanding with IMRT techniques than with 3DCRT or with conventional radiotherapy.34 However, more
and more reports have been published from clinical
departments reporting their experience with the
introduction of clinical and dosimetric quality-assurance
programmes for IMRT.35,36 The quality assurance needed
does not differ substantially between a dose plan
prescribed on the basis of theragnostic imaging and that
prescribed on the basis of a limited number of specified
point dose constraints. The possible increase in
radiation-induced second cancer in long-term survivors
after IMRT remains controversial. In a review, Hall and
Wuu37 pointed out that the change from conventional
radiotherapy techniques to 3D-CRT is expected to reduce
the incidence of radiation-induced cancers as a result of
the relative decrease in the healthy-tissue volume
receiving high doses of radiation. However, a change
from 3D-CRT to IMRT typically involves an increase in
the number of fields used. Furthermore, because a large
proportion of the radiation field is shielded by the
collimator during irradiation, the time for which the
accelerator beam is switched on will increase by a factor
of two or three. This feature will increase the total body
Prostate tumour T2* relaxivity
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Frequency
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R2* (s–1)
Normo-oxic
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Anoxic
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Dose in 35 factions (Gy)
Courtesy of N J Taylor, D Carnell, and A Padhani, Mount Vernon Hospital, UK
Although much research is needed before dosepainting can be introduced into clinical practice, the
issue is whether this step is far enough. The problem
with discrete volumes is that they are binary: voxels are
either inside or outside the volume. However, the
clinical and biological reality is that there are gradients
of oxygen tension or three-dimensional distributions of
the density of radioresistant cellular phenotypes. This
discrepancy led me to propose a more radical change in
the way theragnostic imaging can be used in prescribing
four-dimensional dose distributions—dose-painting by
numbers. Named after the painting-by-numbers
activities in children’s activity books, the principle is
illustrated in figure 2 in a patient with localised prostate
cancer, a tumour type characterised by regions with
substantial hypoxia.32 The clinical target volume,
typically defined on a CT or MR scan, is transferred to
the BOLD MR scan, and an intensity histogram is
calculated for the marker of hypoxia. These intensities
will correspond to voxel oxygenation status covering the
full range from normal to anoxic. The non-linear scale
indicates the prescribed dose as a function of marker
intensity. A lower boundary of 70 Gy ensures that no
part of the tumour will have a prescribed dose lower
than the standard prescription. An upper boundary of
85 Gy is defined to limit the dose to any structure in the
patient, and this value is repeated in figure 2 to indicate
that it is a ceiling on the prescribed dose. Then, all of the
prescribed doses on a pixel-by-pixel basis are used to
specify the desired dose distribution in inversetreatment-planning software. The technical feasibility of
this procedure was shown by Alber and colleagues,33
who modified their inverse-planning software to
implement dose-painting by numbers on the basis of
18
F-misonidazole imaging data.
Figure 2: BOLD MR image of a patient with prostate cancer
The region of interest was defined from haematoxylin-eosin staining of the prostate sections and transferred to the MR image. The distribution of R2* values in the
region of interest covers the range of oxygenation status from normal to anoxic. Dose-painting by numbers involves the prescription of a specific, physically absorbed
dose of radiation on a voxel-by-voxel basis according to a defined prescription function as indicated by the non-linear scale below the histogram.
http://oncology.thelancet.com Vol 6 February 2005
115
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exposure owing to leakage radiation. Hall and Wuu
estimate that IMRT will increase the frequency of second
cancers in patients surviving for 10 years to 1·75%
compared with 1·00% after conventional radiotherapy.
10-year survival in most solid cancers is below 50%, so
this higher rate corresponds to an increase of less than
0·5% in all cases treated. Clearly, this effect will be
outweighed by any clinically relevant gain in control of
the primary tumour resulting from IMRT. Hall and Wuu
underlined the uncertainties in these estimates, but they
must be regarded as current best values. The issue of
radiation-induced second cancers will be most important
in children and other patients with long life expectancy.
Again, there is no major difference between standard
IMRT and IMRT prescribed by dose-painting by
numbers.
Are we ready for dose-painting by numbers?
Validation of the imaging target is the first objective in
building the case for a new theragnostic imaging
procedure. This aim generally involves two steps. The
first is to show that the imaging variable correlates with
a local biological property, such as a local microelectrode measurement of oxygen tension for hypoxic
imaging or a mitotic index or a Ki-67 labelling index for
imaging of cell proliferation. The second step is to show
the clinical importance of the validation marker for the
radiobiological characteristic in question; for example,
that the Ki-67 labelling index actually selects for a
benefit from accelerated radiotherapy. This step might
at first seem superfluous, but it is needed to justify the
prescription of a specific temporal modulation of
radiotherapy based on the imaging information.
Even with a validated imaging target, temporal stability
is a concern. The usefulness of theragnostic imaging in
prescribing four-dimensional dose distributions
obviously depends on the short-term and long-term
stability of the three-dimensional map of density of
specific cellular phenotypes or microenvironmental
variables. Oxygenation is one example: intermittent
closing and opening of vessels can cause microscopic
changes in oxygenation, so-called acute hypoxia, on a
typical time-scale of minutes.38,39 The extent to which this
process affects hypoxia as estimated with radionuclidelabelled compounds is not clear. In addition, there is
reoxygenation of hypoxic regions after the radiation cell
killing a few hours after each dose fraction and
throughout the full 6–7 weeks of fractionated
radiotherapy. Even if reoxygenation does occur, boosting
of the radiation dose to the region that was hypoxic at the
start of therapy can still be worthwhile. Studies of the
temporal stability of hypoxia maps are in progress in
several centres.
Spatial resolution is poorer with PET, SPECT, and MR
spectroscopy than with MR imaging and CT and there
can be difficulties with partial volume artefacts. At
present, commercial high-resolution clinical PET
116
Search strategy and selection criteria
Data were identified by searches of PubMed using the search
terms “radiotherapy or radiation oncology”, “functional
imaging”, “molecular imaging”, “positron emission tomography”, “magnetic resonance imaging”, and “magnetic
resonance spectroscopy”.
scanners have a full width at half-maximum resolution
of 3·5–5·0 mm in both the axial and transverse planes.
The development of CT-PET and MR-PET scanners
might help in reducing the partial volume artefacts and
could improve the accuracy of image coregistration. By
contrast, the achievable resolution with current PET
scanners should be seen on the scale of achievable
spatial precision in delivering 35 dose fractions in the
clinic. This requirement defines an effective limit on the
steepness of gradients that are deliverable in the clinic,
which, with current radiotherapy technology, is probably
not much better than the above 3–4 mm. Clearly, dosepainting by numbers will need optimum precision of the
planning dosimetry and the multileaf-collimator
technology as well as immobilisation of the patient and
reproducibility. Physiological organ movement is
another possible limitation that is being addressed by
several research groups.
The final, hugely challenging, topic of research is to
establish the prescription function that is the
mathematical link between a specific value of an
imaging variable and the optimum clinical dose to be
prescribed to the corresponding voxel. This function is
unlikely to be defined from radiobiological measurements made in vitro but will have to be derived from
outcome data in human beings or in animals. Ideally,
evidence-based prescription rules should be derived
from controlled clinical trials. Simple linear
interpolations between a clinically justified minimum
and maximum dose over the range of values covered by
the imaging variable might suffice as a first
approximation, but strategies are under investigation
that could further refine this prescription function.
In conclusion, theragnostic imaging for radiation
oncology will revolutionise the whole process of
radiotherapy prescription and planning. At the present
rate of progress, a realistic prophecy is that this
therapeutic principle will be in early clinical testing
within the next 5 years.
Conflict of interest
I declare no conflicts of interest.
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