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Editorial
The role of molecular imaging in precision radiation therapy
for target definition, treatment planning optimisation
and quality control
Giovanni Lucignani1, 2, Barbara A. Jereczek-Fossa1, Roberto Orecchia1, 2
1 Unit
of Molecular Imaging, Department of Radiation Oncology, European Institute of Oncology, Milan, Italy
of Radiological Sciences, University of Milan, Milan, Italy
2 Institute
Published online: 30 March 2004
© Springer-Verlag 2004
Eur J Nucl Med Mol Imaging (2004) 31:1059–1063
DOI 10.1007/s00259-004-1517-x
During the past decade, remarkable technological developments have led to major improvements in treatment
planning, dose delivery and quality assurance in radiation therapy. In particular, radiation therapy planning has
evolved considerably through three phases based on the
strategies used for tumour targeting. Planning was initially based on the use of clinical judgement and external
visible markers (one-dimensional planning). The introduction of the simulator resulted in planning based on
the radiographic anatomy, allowing bi-planar isodose
distribution (two-dimensional planning), with better
beam shaping and normal tissue avoidance and sparing.
The recent development of new algorithms for threedimensional (3-D) reconstructions of anatomy, dose calculation and radiation delivery has made it possible to
precisely sculpt the radiation dose to target volumes of
almost any shape. This progress has initiated the era of
3-D conformal radiation therapy (CRT), intensity-modulated radiation therapy (IMRT) and intensity-modulated
arc therapy (IMAT). These new modalities, along with
brain and extracranial stereotactic irradiation (SRT),
modern brachytherapy and particle radiotherapy (with
hadrons, such as protons and ions), have become forms
of high-precision radiation therapy. In 1993, the International Commission on Radiation Units and Measurements (ICRU) published the first report on the definition
of target volumes: the gross tumour volume, i.e. the volGiovanni Lucignani (✉)
Unit of Molecular Imaging, Department of Radiation Oncology,
European Institute of Oncology, Via Ripamonti 435,
20141 Milan, Italy
e-mail: [email protected]
Tel.: +39-02-57489037
ume that includes the demonstrable extent and location
of the primary tumour, regional lymph nodes and distant
metastases; the clinical target volume, which includes
the gross tumour volume and/or the sites of subclinical
disease, and the planning target volume, a volume determined by including any geometric uncertainties and setup margins [1]. The report was subsequently updated in
1999 [2]. In the 1999 supplement an internal target volume, reflecting the motion of the clinical target volume,
was added, and the use of a safety margin around the
organ at risk was also recommended, generating the
planning organ at risk volume. However, the above concepts were defined at a time when precision radiation
therapy techniques were still in a preliminary phase.
With the increasing use of modern radiation delivery
techniques, which permit a degree of precision in the delivery of the dose to the target that had never been
achieved before, a major change in the accuracy of tumour localisation procedures is also essential. Among
the various tools needed for such a high-precision radiation procedure, imaging techniques have become crucial
for clinical practice.
Target volume definition and characterisation
There is no doubt that precision radiation therapy techniques require accurate tumour identification and delineation. Inaccurate assessment of the target can lead to
failure to meet the treatment goals, with a higher probability of tumour recurrence and an additional, unnecessary radiation burden. At present, anatomical imaging is
the basis of treatment planning. Computer tomography
(CT) has become the reference imaging modality for
treatment planning owing to its acceptable costs, wide
availability, absence of geometric distortion and inherent
ability to provide information on tissue density, which is
useful for dose calculation. The use of magnetic resonance imaging (MRI) allows better target volume definition compared with CT in some specific sites and pro-
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vides multi-plane images, facilitating the assessment of
tumour extension. MRI images, however, may be degraded by geometric distortion at the edge of the field of
view and do not allow precise delineation of the external
contour of the body and of the bony structures. Moreover, the use of MRI for the purpose of treatment planning is limited by the absence of information on tissue
density. Although some of the above limitations can be
overcome by CT-MRI image fusion, both CT and MRI
provide accurate yet mainly morphological information.
Progress in molecular imaging, mostly based on positron
emission tomography (PET) and MR-spectroscopy, may
allow the incorporation of crucial functional, biological
and molecular images in radiation therapy practice on a
regular basis [3].
The present role of PET
PET is currently used in oncology for staging, follow-up
and, to a limited degree, assessment of therapy response.
So far attention has been focussed mostly on imaging of
glucose uptake with fluoro-2-deoxy-D-glucose (FDG). It
has been demonstrated that the use of FDG-PET can
result in a change in staging, and thus patient management, in about 20–30% of cancer patients, including
those waiting to undergo radiation therapy [4, 5]. However, beyond these applications there are new areas for
the use of PET that may result in significant improvements in tumour treatment. Assessment of the molecular
and functional features of tumours by means of PET may
allow the definition of local features that can be exploited in order to focus the treatment strategies. Tumour
masses are never homogeneous with respect to many
features that may not appear on CT images or appear
only as variations in tissue density, including viability
and necrosis, vascularisation and oxygenation, rate of
cellular growth and apoptosis, and receptor and antigen
expression. All of these features determine the malignancy and evolution of the tumour, and in principle their
assessment could be extremely useful for precision radiation therapy planning. Thus, tumour tissue characterisation by PET has become a major goal. Various PET procedures are currently being tested in numerous centres
worldwide, with extremely interesting and promising
results.
It is well established that the detection of hypermetabolic tumour tissue by FDG-PET may lead to better definition of the clinical target volume, i.e. the local and
regional extension of the neoplastic disease [6, 7, 8, 9,
10, 11]. In addition, it can be hypothesised that different
target volumes may be identified within the same tumour
mass, based on the level of FDG uptake. Areas of high
FDG uptake can then be treated with a higher radiation
dose compared with the hypometabolic portions of the
same mass. This is of particular value for IMRT and active scanning proton therapy as sub-volumes of each sin-
gle target can be irradiated with different radiation dose
levels in a single treatment session. FDG-PET scanning
could also help to identify areas for dose escalation protocols based on the biological assessment of the tumour
mass. Furthermore, as hypothesised by Brahme [12],
biological information on the tumour radio-responsiveness, evaluated by FDG-PET after a week or two of
treatment, might be employed for modification of the
initial treatment plan, thereby extending the concept of
so-called adaptive radiation therapy.
Merging molecular and anatomical imaging
for precision radiation therapy
PET images alone cannot provide anatomical information, thus precluding the use of PET as a single imaging
modality for the purpose of treatment planning. For this
reason, the combination of at least two imaging modalities, PET and CT, has been examined [13, 14, 15]. Various methods for PET-CT fusion have been developed
over the years, based on the use of spatial co-registration
techniques by interactive or automated methods, including landmarks, surface or voxel co-registration, and rigid
or warping algorithms. However, the real revolution in
image fusion has occurred recently with the introduction
of PET-CT scanners [16, 17]. It has already been demonstrated that integration into 3-D simulation and treatment
planning of fused CT and PET images can improve the
accuracy of radiotherapy planning and dose delivery and
may result in a substantial reduction in the irradiation of
normal tissue due to improved tumour delineation [18,
19, 20, 21]. For example, in patients with non-small cell
lung cancer, the use of FDG-PET helps to exclude areas
of atelectasia or infection from the target volume, while
permitting an increase in the treated volume to incorporate regional lymph node lesions detected by virtue of
their FDG uptake [22].
In an attempt to reduce both false positive and false
negative PET findings with FDG, several other tracers
have been developed for tumour assay. The uptake of
methionine in tumours has been related to the rate of
amino acid transport, methylation and incorporation into
proteins and is considered to offer a non-specific index
of tumour viability. In particular, methionine may be
more useful than FDG in brain tumours, owing to the
high glucose metabolism of normal nervous tissue [23].
The use of another amino acid, thymidine, has been
evaluated for the assessment of cell proliferation based
on its incorporation in DNA. A thymidine analogue, 3′deoxy-3′-[18F]fluorothymidine (FLT), has been used for
visualisation and quantification of cellular proliferation
[24, 25]. FLT is a substrate for phosphorylation by TK-1,
an enzyme that is highly expressed in rapidly proliferating malignant cells during DNA synthesis. Thus, FLT
accumulation in the cell is considered a measure of the
TK-1 expression.
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With respect to tissue characterisation, a major expectation is that new and more specific radiolabelled tumour
markers which allow even more accurate imaging of
tumour clonogen density will become available to complement the information gained by FDG. Major results
are expected from the development of PET tracers for
the evaluation of hypoxia, angiogenesis, apoptosis and
mutant p53 [12, 26, 27]. All these variables play an important role in determining the outcome of radiation
therapy. For example, hypoxia is a well-known cure-limiting factor in radiotherapy. Thus, PET-based identification and quantification of tumour hypoxia may predict
radiotherapy outcome and may identify patients who
might benefit from concurrent radiosensitising therapies
to overcome the hypoxia effect [28]. The most extensively studied agent for PET imaging of hypoxia is
18F-MISO, a misonidazole derivative labelled with fluorine-18. However, it has been shown that this is a suboptimal tracer owing to its kinetic properties. A novel approach based on the use of positron emitting isotopes
of copper (Cu-60, Cu-62, Cu-64), diacctyl-bis(N(4)methylthiosemicarbazone (ATSM) has been proposed to
overcome the limitations of 18F-MISO. A strong correlation between low tumour pO2 and excess 60Cu-ATSM
accumulation has been demonstrated. Preliminary studies have also confirmed the feasibility of 60Cu-ATSMguided IMRT following co-registration of hypoxia
60Cu-ATSM PET images to the corresponding CT images for IMRT planning [29].
In the search for tools for tissue characterisation, the
potential value of several different tracers aimed at targeting different markers of the angiogenic process has
been appraised. One of the most interesting approaches
is based on the assessment of the integrin alpha-v/beta-3,
a transmembrane glycoprotein involved in the migration
of activated endothelial cells during formation of new
vessels. However, translation of these approaches into
clinical settings is still awaited [30].
Another approach to tissue characterisation is based
on the assessment of apoptosis. Lack of apoptosis is a
hallmark of several human tumours; thus, imaging methods for the evaluation of apoptosis have been sought,
mostly based on assessment of the externalisation of
phosphatidylserine resulting from the deactivation of
translocase and floppase, together with activation of
scramblase [31]. The possibility of assessing apoptosis
by annexin V is under validation [32, 33]. Annexin V is
a 36-kDa calcium-dependent phospholipid-binding protein which has a high affinity for the membrane phospholipid phosphatidylserine. To this end, labelling with
18F is being pursued, in the form of N-succinimidyl 418F-fluorobenzoate ([18F]SFB). Annexin V has also been
labelled with iodine radioisotopes, and initial results
have shown that the binding of N-succinimidyl-3iodobenzoic acid (SIB) derivative of annexin V, labelled
with radio-iodine to radiation-induced fibrosarcoma
(RIF-1) tumours is increased by 5-fluorouracil adminis-
tration, providing evidence of the potential usefulness of
this approach. In a recent study, the relationship between
quantitative 99mTc-6-hydrazinonicotinic (HYNIC) radiolabelled annexin V tumour uptake and the number of tumour apoptotic cells derived from histological analysis
has also been examined [33].
Conclusions and future outlook
It has been shown that the incorporation of FDG-PET
data improves definition of the primary lesion, may enhance the precision with which modern radiotherapy
modalities (3D-CRT, IMRT, IMAT, SRT, brachytherapy,
hadron therapy, etc.) is delivered to patients, reduces the
likelihood of radiation treatment misallocations, allows
for dose escalation and boost delivery to the more radioresistant tumour areas, and hopefully improves the
chance of achieving local control [34, 35, 36, 37]. It
seems probable that PET scanning and other functional
imaging techniques will play a major role in the definition of tumour extent and staging of cancer patients.
Studies on PET as a predictor of response to radiotherapy
are promising; however, optimisation of the pharmacokinetics of the PET radiopharmaceuticals and their validation against gold standard tests will be necessary. At this
time it is still difficult to fully evaluate to what extent
PET or other imaging studies may help in representing
the heterogeneity of tumour masses. Better understanding
of molecular biology and genetics should further elucidate the correlation between tumour parameters assessed
by molecular imaging and response to radiation therapy.
The correlation of pathological findings and imaging results will permit validation of the accuracy of the molecular imaging approach to tissue characterisation. Furthermore, clinical outcome studies will be necessary to establish the value of molecular imaging in delineating target
volumes and, eventually, in improving patient outcome.
Prospective studies are necessary to determine whether
better local control and lower toxicity are achievable with
the use of molecular imaging-based techniques.
There is a further potential use of PET for dose optimisation and quality control. In fact, PET is already being experimentally used to verify the integral dose delivered during treatment with high-energy photons
(20 MeV or more) and protons as they can produce positron-emitting radionuclides by interacting with living
matter components. The photonuclear reaction in tissue
is proportional to the fluence and thus to the absorbed
dose. Also, light ion beams produce positron-emitting
radionuclides through direct nuclear reactions in tissue.
These positron-emitting radionuclides allow PET imaging of the Bragg peak distribution. This use of PET
could complement the present physical measures to assess the absorbed dose, by providing information on the
actual nuclear reactions occurring in the target volume as
a result of the radiation delivered [12].
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Precision radiation therapy and molecular imaging
share an exciting future. The impressive advances in the
field of imaging technology, represented by high-resolution multimodality imaging techniques dedicated to oncology [38], and the development of new tracers for
molecular imaging represent two crucial pillars for the
future of precision radiation therapy. It is becoming conceivable that a radiation therapy simulator with multimodality imaging capability could be used, and beyond
this, that systems could be developed which enable the
performance of PET-CT imaging by a single complex
device during the delivery of an intensity-modulated
dose, thereby achieving imaging during the treatment
session. This might become possible by exploiting the in
vivo nuclear reactions and gamma-emitting radionuclide
production that occur during the therapeutic irradiation
of tumours. Finally, the combination of molecular imaging and precision radiation therapy is likely to enable
each of the multiple sites of secondary tumour diffusion
to be treated with a discrete dose, and to allow treatment
of cancer patients in more advanced disease stages.
11.
12.
13.
14.
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