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PET-CT based Radiotherapy Treatment Planning372
standardization of volume delineation compared with that of CT alone. The combination of
these imaging modalities improves diagnostic accuracy and localization of many lesions. It
has been shown that in extracranial sites, PET scanning should only be performed with a
dedicated PET-CT device because present image fusion technologies are inadequate for
accurately registering deformable objects (3).
The concept of multimodality imaging improves the ability of earlier detection of the
tumor volume. Though it is quite often used for identification of tumor volume and to assess
the treatment response in medicine, it plays a vital role in radiotherapy especially as radiation
treatment planning tool and for treatment verification. In order to combine all this information
and incorporate it into the treatment planning process, 3-D image registration is needed.
Image registration is basically a computer tool, which is able to match the 3-D spatial
information of the different imaging modalities by use of either external fiducials or internal
anatomic landmarks.
Image registration
Accuracy of image registration is an important factor in radiotherapy treatment planning
and any discrepancy in the fused images has significant impact on the probability of tumor
control and on the normal tissue complication. The images may have different alignments in
space; different pixel spacing and anatomic structures may differ. Hence, image registration
algorithm should provide a perfect match of anatomic structures from the imaging modalities
registered. Registrations of multimodality images were based on either external markers or
mutual information. Image registration is done for stand-alone PET and CT images or for
integrated PET-CT images. The advantages of PET-CT over stand-alone PET and CT are
that PET-CT offers more accurate localization of FDG uptake, the distinction of pathological
from physiologic uptake, and improvements in treatment monitoring.
In PET-CT image registration, one of the factors that contribute to the errors is couch
sag as patient is moved form CT to PET scanning position. It can be addressed by using
carefully designed couch. In order to use the PET-CT data for radiotherapy treatment planning,
the scanner must be equipped with a flat-bed insert as the radiotherapy treatments are
performed with patients on a flat couch. The bore size of the scanner should have sufficient
space to accommodate the patient with immobilization device. The limitations of PET-CT
image registration include the artifacts induced by patient movement, respiratory motion, or
from metallic dental implants. Respiratory or patient motion induces artifacts on both CT
and PET images and therefore, on the composite PET-CT images. Clinical challenges exist
in co-registering CT and PET image modalities in cases like respiration and the study of
blood flow under stress. The newly available hybrid PET-CT scanners are very popular and
have removed many of these misalignments; breathing-related non-rigid mismatches still
persist.
PET-CT based Radiotherapy Treatment Planning 373
Ireland et al. (4), have shown that for patients with head and neck cancer, non-rigid
algorithm provide a more accurate registration of PET-CT to radiotherapy planning CT than
rigid registration. The authors have also shown that non-rigid registration of PET-CT acquired
with patient in a standardized, diagnostic position can provide images registered to planning
CT with greater accuracy than a rigid registration of PET-CT images acquired in treatment
position. For suitable patients, this may enable a staging PET-CT, rather than a treatment
position PET-CT, to be used in radiotherapy treatment planning (4).
Most of the published papers have chosen to define regions based upon a percentage of
the maximum standardized uptake value (SUV) (5) for the object under consideration or
based upon a percentage contour within the image or any absolute value of the SUV (6,7).
These regions are normally drawn manually and do not immediately address the issues
discussed above or signal-to-noise ratio within the images themselves. In addition, the nontarget activity levels will impact upon the derived volumes (8). Despite these uncertainties,
PET data are being used within the radiation treatment planning process and volumes modified
are according to the PET distribution (9).
The rational use of PET in radiation treatment planning depends on the qualities of PETCT like sensitivity, specificity, positive predictive value, negative predictive value and accuracy
of PET and CT. These qualities depend on the specific tumour site (10, 11). During planning,
maximum SUV, volume, mean dose received should be recorded for regions-of-interest
(ROI), as these parameters are very useful for comparing the follow-up scans. The imaging
of hypoxia, cell proliferation, angiogenesis, apoptosis and gene expression leads to the
identification of different areas of a biologically heterogeneous tumor mass that can
individually be targeted using intensity modulated radiotherapy (IMRT).
Dose calculation formalism requires anatomic information in terms of electron density
ratios, which can be obtained only from CT images. Information derived from a variety of
other sources may also be needed. Three-dimensional anatomic information obtained from
CT images forming a 3-D matrix of CT number is essential for 3-D dose calculations.
Three-dimensional radiotherapy treatment planning systems allows the clinician to define
tumor and normal anatomy from CT scans and project the results onto a digitally reconstructed
radiograph (DRR) for comparison with the simulation or portal film. They can also be used
for comparison of different plans in a single plot and produce measures of tumor control
probability and normal tissue complication probability allowing quantitative scoring and
evaluation of plans. The display of various statistics that summarizes the treatment plan
(minimum and maximum dose within volumes, dose which at least 5% or 95% of a volume
receives, etc.,) also assists in the plan evaluation. In evaluating any plan, it is important to
realize that what matters is not what is planned but what is actually delivered.
Clinical applications of PET-CT in radiotherapy
It is generally accepted that imaging the metabolic activity of tumour tissue provides
PET-CT based Radiotherapy Treatment Planning374
more sensitive and more specific information about the extent of disease than morphologic/
anatomical imaging alone. FDG-PET is primarily used for staging different types of cancer,
including head and neck cancer, lung cancer, breast cancer, colorectal cancer, lymphoma,
and melanoma (12). PET has also been found to have significant impact on the delineation
of tumor volume in esophageal carcinoma (13). The quantitative assessment of changes in
tumour metabolic activity provided by FDG-PET allows monitoring of response to cancer
treatment (14). Such changes are often detected before morphological changes are seen by
conventional imaging modalities.
Some of the Medicare approved indications for PET are non-small cell lung cancer
(NSLC), colorectal cancer, melanoma, esophageal cancer, lymphoma, head and neck cancer,
and solitary pulmonary nodule. Thyroid cancer, breast cancer and cervical cancer are also
approved by Medicare as indications for PET with some restrictions. Choline PET and
acetate PET are promising tracers in the diagnosis of prostate cancer, but their validity in
local tumor demarcation, lymph node diagnosis and detection of recurrence has to be defined
in future clinical trials. In high-grade gliomas and meningiomas, methionine PET helps to
define the GTV and differentiate tumor from normal tissue. In case of breast cancer, PET
can be used for staging or restaging of suspected advanced disease but cannot be used for
initial diagnosis.
PET radiotherapy planning in NSLC
FDG-PET has a significant impact on GTV and PTV delineations in lung cancer and can
detect lymph node involvement and differentiate malignant tissue from atelectasis. In case
of NSLC, CT and PET are complementary and should be obtained in the treatment position
and fused to define the GTV. Although the quantitative absolute target volume is sometimes
similar, the qualitative target locations can be substantially different, leading to underdosage
of the target when planning is done using CT alone without PET fusion (15). But there are
studies showing that limiting the target volume to predominantly PET-positive disease resulted
in a low rate of isolated out-of-field recurrences (16). Hence for NSLC, combined information
of PET and CT or information from the fused PET-CT significantly improves the treatment
response (17). It is recommended that FDG-PET data should be integrated into treatment
planning of NSLC, particularly for three-dimensional conformal techniques (18). In patients
with NSCLC considered for curative radiation treatment, assessment of loco-regional lymph
node and tumour extension by PET will improve tumour coverage, and in selected patients,
will reduce the volume of normal tissues irradiated (19). Integrated hybrid PET-CT scan in
the treatment position and coregistered images have been found to have impact on treatment
planning and management of non-small-cell lung cancer. However, 18F-FDG images using
dedicated PET scanners and respiration-gated acquisition protocols could improve the PETCT image co-registration (20).
PET-CT based Radiotherapy Treatment Planning 375
PET-CT in Head and Neck cancer
The addition of PET-CT to GTV (primary site) delineation of head and neck cancers
does not change the volume of the GTV as observed on CT but it may demonstrate differences
in neck node delineation and in other disease sites (21). Schwartz et al (22) shown that the
addition of 18F-FDG-PET is superior to CT alone in geographic localization of diseased
neck nodes, with sensitivity of 96% and specificity of 98.5% in nodal level staging. FDGPET has also been demonstrated to be a prognostic indicator of recurrence in head and neck
cancer (23). Results such as these have spurred investigators to evaluate the utility of FDGPET for target volume delineation in head and neck cancers. Patients diagnosed with
oropharyngeal carcinoma might particularly benefit from PET-CT-guided IMRT because
oropharyngeal tumors are often difficult to identify by CT scan alone. In head-and-neck
cancer, the value of FDG-PET for radiation treatment planning is still under investigation. It
could be superior to CT and MRI in the detection of lymph node metastases and unknown
primary cancer and in the differentiation of viable tumor tissue after treatment.
PET in brachytherapy
PET-CT finds a place not only in external beam radiotherapy but also in brachytherapy.
PET imaging has just recently been approved for use in the initial staging of cervical cancer;
however, restaging with PET is not yet approved. PET images may allow more accurate
delineation of three-dimensional treatment planning target volumes of brachytherapy
gynecologic implants. As brachytherapy is shifting from the conventional two-dimensional
‘points’ to three-dimensional ‘profiles’ for targets and normal tissues, the utility of sequential
FDG-PET imaging for brachytherapy treatment planning in patients with carcinoma of the
cervix has helped in evaluating the tumor response in individual patients potentially making
patient-specific brachytherapy treatment planning possible (24). PET-CT images have the
potential to provide better spatial information about the relationship of tumor and normal
structures to the applicator. This information can be used to optimize the delivery of radiation
therapy treatments. Studies have revealed that FDG-PET based treatment planning allowed
for improved dose coverage of the tumor without significantly increasing the dose to the
bladder and rectum (25-27). Studies have also revealed that FDG-PET can be used for
evaluation of physiological tumor volume response during treatment in cervical cancer (28).
FDG-PET has revealed a 50% physiologic tumor volume reduction within 20 days of starting
radiotherapy in cervical cancer (28, 29). Sakurai et al 2006 has showed that FDG-PET is a
useful tool for the detection of extrapelvic lesions during the follow-up period in cervical
cancer and stated that FDG-PET has limitations in the detection of lesions less than 1cm3 or
microscopic disease. Hence, careful diagnostic agreement between PET and CT/MRI for
positive but benign lesions, such as inflammation and bone fracture, remains important.
FDG-PET also been shown as a reliable and accurate diagnostic tool for detecting recurrent
or metastatic gynecologic cancer particularly lymph node metastases (30). It seems to be
valuable in lymph node status definition in cervical cancer.
PET-CT based Radiotherapy Treatment Planning376
PET-CT for dose escalations and mapping of hypoxic lesions
As sensitivity of tumor cells to radiation differs according to pathology, differential
doses need to be delivered to the tumor. The only solution is the simultaneous integrated
boost technique (SIB). In head and neck cancer, focal dose escalations based on PET findings
were found to give better results. IMRT performed with PET-CT scanning allows dose
escalation to biologically active subregions within the tumor volume (3).
In radiotherapy, higher tumor control probability can be achieved by escalating the dose
to the target volume if the tumor volume is accurately defined. An important concern in
radiotherapy is the presence of hypoxic cells. Since hypoxic cells are resistant to radiotherapy,
it requires dose escalation for eradication of these cells. The current concept in radiotherapy
is dose painting by numbers (DPBN). Dose painting by numbers is based on the map of
dose-escalation factors calculated from dynamic 18F-fluoromisonidazole (FMISO) positron
emission tomography data (31). 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. 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 (32).
PET-MRI scanner
Although CT remains the gold standard for radiotherapy planning, MRI has much to
offer. Superior soft tissue characterization and new developments in dynamic contrast
enhanced, diffusion-weighted and diffusion tensor imaging are making their mark in target
delineation. Magnetic resonance spectroscopy promises insights into tissue metabolism and,
although currently limited by large voxel sizes, may provide information on tumour response
and recurrence to complement the structural information of MRI and CT.
The use of multi-modality imaging fusion and the introduction of more sensitive and
specific PET-CT tracers have revolutionized the field of radiation oncology. Furthermore,
the potential to predict early outcome or even detect early recurrence of tumor has improved
the survival rate of cancer patients.
Conclusion
In the current scenario, the success of radiotherapy is totally dependent on medical
imaging. PET-CT is increasingly being incorporated in radiotherapy. It is a boon for radiation
oncologist for tumor volume delineation in radiation treatment planning and for assessing
the treatment response. Especially in lung cancer, the role of combined PET-CT significantly
influences the target volume definition. However, data on the confirmation of the relation
between delineation based on CT and PET and pathologic examination are lacking in most
of the tumour regions. More research is needed to address the question whether PET does
PET-CT based Radiotherapy Treatment Planning 377
allow accurate tumour delineation in regard to pathological tumour extension. Delivery of
radiation doses according to cell sensitivity is ultimate solution for complete eradication of
tumor cells. Higher resolution PET and CT components need to be developed for radiotherapy
treatment planning. For patient comfort, the duration of PET-CT imaging acquisition should
be decreased. The anatomical detail given by MRI and the spectroscopy detail of magnetic
resonance spectroscopy (MRS) complement the quantitative physiological imaging obtained
with PET. Hence a combined PET and MRI scanner will further improve the treatment
planning and its outcome in radiotherapy.
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PET Imaging: Potential Applications
in Gene and Stem Cell Therapy
Tarun Singhal
Positron Emission Tomography is a state-of-the-art imaging technology developed to
use compounds labeled with positron emitting radioisotopes as molecular probes to image
and measure biochemical processes in vivo (1). The positron emitting radioisotopes of oxygen
(14O, 15O), nitrogen (13N), carbon (11C), and fluorine (18F, as a substitute of hydrogen) are
used to label biomolecules to track biochemical processes. This is a significant advantage
over the conventional radiotracer methods, which use bulky radioisotopes and thus, alter the
in vivo behavior of the labeled biomolecules.
Gene therapy and Stem Cell therapy lie at the cutting edge of therapeutics research in
medicine. Gene therapy uses introduction of genetic material into cells to repair or treat
disease. On the other hand, stem cell therapy involves administration of pluripotent renewable
cells to organs irreversibly damaged by disease. The two disciplines are now converging as
stem cells are being genetically modified before being transplanted in the diseased organs to
achieve a constant, renewable source of desired biological functions.
PET imaging has the potential for contributing in these endeavors at both the preclinical as well as clinical stages. Micro-PET is a powerful modality for imaging gene
expression in small animals at the pre-clinical stage. The aim of this chapter is to explore
and provide a conceptual outline of the potential applications of PET imaging in gene
therapy and stem cell therapy.
Gene Therapy and PET
The concept and terminology associated with PET imaging in gene therapy can be best
explained with the help of an example. However, before going to the specific example, the
areas of potential clinical applications involving gene therapy are summarized in table 1.
38 0
PET Imaging: Potential Applications in Gene and Stem Cell Therapy
Table 1: Potential Clinical Applications in the field of gene therapy
1. Oncology
Tumor suppressor genes e.g. p53
Suicide genes e.g. HSV-tk
Anti-tumor immunotherapy
2. Monogenetic disease
ADA deficiency
Cystic fibrosis
Familial hypercholesterolemia
Hemophilia B
3. Neurodegenerative disorders and Parkinson’s disease
4. Vascular disease
Coronary artery restenosis
Peripheral vascular disease
Hypertension
5. Infectious diseases
Viral diseases
381
Also, as mentioned earlier, gene therapy involves introduction of genetic material into
cells to repair and treat disease. Vectors are agents used to transfer the desired genes into
cells. Genetically modified viruses, and non-viral vectors can be used to transfer desirable
genetic material into cells both inside (in vivo) and outside the tissues (ex vivo), as summarized
in tables 2 and 3.
Table 2: Approaches to gene transfer
Approach Comments
1. Ex vivo gene transfer Genes are transferred into cells that are subsequently introduced into the
patient
Disadvantage: Many tissues are not accessible
2. In vivo gene transfer Genes are directly introduced into tissues
Disadvantage: Non-specific targeting, Irregular gene expression, toxicity
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