Chapter 18.

FUNCTIONAL IMAGING IN HEAD

AND NECK CANCER
EMERGING TECHNOLOGY
THOMAS YANG, MD, K. S. CLIFFORD CHAO, MD

The twentieth century witnessed the advent and develop-
ment of radiography, computed tomography (CT), and
magnetic resonance imaging (MRI), all of which have
enabled physicians to visualize both pathologic and nor-
mal anatomy in a way that was never before possible. Major
advances have also occurred in nuclear medicine with the
development of positron emission tomography (PET) and
single photon emission computed tomography (SPECT).
The standard radiologic images (CT, MRI) provide anatom-
ic information, whereas biologic images (PET, SPECT) pro-
vide metabolic, physiologic, genotypic, and phenotypic
data. Important to the practice of oncology have been the
numerous radioisotopes that have become available. For
nuclear medicine, these can provide critical information
on the metabolism and function of different tumors.
Radiation oncology has been a beneficiary of the
progress in imaging technology. In particular, biologic
imaging has had a tremendous impact on intensity-
modulated radiation therapy (IMRT) because IMRT allows
the delivery of different doses of radiation to multiple tar-
gets. Important to an understanding of IMRT is the con-
cept of the biologic target volume first proposed by Ling
and colleagues (Figure 18.6-1).1 The important advantage
of IMRT is that normal tissue is spared; thus, the side effects
of radiation therapy (RT) can be reduced. For obvious rea-
sons, this capability is particularly useful in the treatment
of tumors of the head and neck.
The purpose of this chapter is to discuss the current appli-
cations of functional imaging in head and neck cancer IMRT
planning and the monitoring of treatment response. Future
directions in functional imaging are also discussed.
Nuclear Medicine Modalities
Nuclear medicine, and in particular 18fluorodeoxyglu-
cose positron emission tomography (18FDG-PET), is the
functional imaging method most commonly used in head
and neck cancer. 18FDG-PET is used both to stage patients
and to monitor their therapeutic response (or the lack
thereof). With the advent of hybrid PET-CT scanners,
one can now combine metabolic and anatomic informa-
tion in planning RT, including IMRT. The use of hybrid
scanners is likely to become more widespread in medical
centers throughout the United States.
In this section, the role of 18FDG-PET and hybrid PET-
CT scanners is described in detail. Alternative metabolic
imaging methods are also discussed, namely, methods
employing radiolabeled amino acids and nucleosides. The
noninvasive imaging of tumor hypoxia is also presented.
Interested readers should also refer to Chapter 8,“PET-CT
in IMRT Planning.”
FIGURE 18.6-1. The concept of biologic target volume shown in a man-
ner that incorporates the different aspects of functional imaging, name-
ly, tumor hypoxia, tumor burden, and tumor growth. GTV = gross tumor
volume; IUDR = Iodine 124-iododeoxyuridine; MRI = magnetic resonance
imaging; MRS = magnetic resonance spectroscopy; PET = positron emis-
sion tomography; PTV = planning target volume. (To view a color ver-
sion of this image, please refer to the CD-ROM.) Reproduced with
permission from Ling CC et al.1

307
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18FDG-PET
The long half-life of 18-fluorine (18F) has made 18FDG-
PET the most popular metabolic imaging modality. Its pop-
ularity is also due to the fact that, because tumor growth
requires energy, the marker can be used to determine the
degree of tumor proliferation.
The use of 18FDG-PET in RT planning has been eval-
uated in several studies. Rege and colleagues noted that
local control and survival were improved in patients with
head and neck cancer whose tumors had a metabolic rate
greater than that in the cerebellum.2 These results suggest
that pretreatment 18FDG-PET could be used to predict
which irradiated patients will attain local control. It may
also help identify which patients require combined-
modality therapy or adjusted fractionation schedules.
Brun and colleagues noted that a low metabolic rate of
glucose in primary and metastatic lesions was associated
with local complete response in patients with squamous
cell carcinoma of the head and neck undergoing RT.3 Allal
and colleagues found that patients with head and neck can-
cer who showed a high initial FDG uptake may require
more aggressive treatment (Figure 18.6-2).4
In a recent Radiation Therapy Oncology Group (RTOG)
symposium, the application of hybrid 18FDG-PET–CT
imaging to RT was highlighted.5 An important point made
at this symposium was that delineation of the gross tumor
volume (GTV) is a critical step in RT treatment planning.
However, the visualization of primary and abnormal lymph
nodes and observer variation are key limitations when using
CT alone, as shown by a study of 30 patients with non–small
cell lung cancer presented at the symposium. The first goal
FIGURE 18.6-2. Disease-free survival curves in patients with head and
neck carcinoma who showed a standardized uptake value (SUV) of ≤
5.4 versus ≥ to 5.5 and hence the ability of the SUV to predict the out-
come of radiation therapy in head and neck carcinoma. Reproduced with
permission from Allal AS et al.4
of the study was to determine if hybrid 18FDG-PET–CT
improves treatment planning. The second was to deter-
mine if hybrid 18FDG-PET–CT reduces interobserver vari-
ation. Three radiation oncologists contoured the GTV on
the basis of CT alone; they then did GTV contouring using
PET-CT data, after which separate treatment plans were
generated on the basis of each GTV. Comparison of the
resultant treatment plans revealed that the plans were
changed in seven patients (23%) when metabolic infor-
mation was incorporated. In particular, the fused images
provided better target volume definition owing to the detec-
tion of lymph node involvement and distant metastases by
PET not seen on CT. Hybrid 18FDG-PET–CT was associ-
ated with reduced interobserver variation, as evidenced by
a reduction in the mean ratio of the largest to smallest GTV
from 2.31 (CT alone) to 1.56 (hybrid). It was concluded
that hybrid 18FDG-PET–CT more consistently defines the
GTV in these patients.
To corroborate these findings, Ciernik and colleagues
studied 39 patients with different solid tumors.6 All under-
went CT and FDG-PET using a hybrid scanner. Initially,
the GTV was delineated by two radiation oncologists based
on CT alone. The 18FDG-PET information was then incor-
porated into the CT data, and GTV was again delineated.
The GTV was modified in more than half (56%) of the
patients once the 18FDG-PET information was incorpo-
rated. Moreover, variability in the volumes delineated by
the two radiation oncologists decreased from an average
of 25.7 to 9.2 cm3 (Figure 18.6-3).
Given that multimodality imaging is becoming more
widespread, feasibility and quality assurance issues regard-
ing the coregistration of images have been raised. To address
these issues, Daisne and colleagues studied the accuracy,
reproducibility, and consistency of the coregistration pro-
cedure using a phantom and four patients with pharyngo-
laryngeal tumors.7 In particular, they studied the translation
and rotational displacements relative to a reference CT scan
and found that the coregistration accuracy ranged from 0.8
to 6.2 mm for the phantom and from 1.2 to 4.6 mm for the
patients. The accuracy was only slightly worse in the z-axis,
and inter- and intraobserver variations were small. These
results suggest that the coregistration of anatomic (CT, MRI)
and functional (PET) images is accurate in patients with
head and neck cancer (Figure 18.6-4).
In addition to its utility in treatment planning, 18FDG-
PET has also been shown to be useful in predicting treat-
ment response. Greven and colleagues studied 45 patients
with head and neck cancer who underwent 18FDG-PET
and CT or MRI prior to RT.8 Follow-up studies were
obtained at 1 month (36 patients), 4 months (28 patients),
12 months (19 patients), and 24 months (15 patients). At
4 months, none of the 18 patients with a negative pre-
treatment 18FDG-PET had persistent tumor, whereas 6 of
7 patients with positive pretreatment findings had persis-
tent tumor and 2 of 3 with equivocal findings had positive
 Functional Imaging in Head and Neck Cancer: Emerging Technology / 309

FIGURE 18.6-3. Treatment plans for a patient with supraglottic carcinoma generated based on computed tomography (CT) alone (A) and positron
emission tomography (PET)-CT (B). Axial section through tumor showing gross tumor volume delineated from CT alone (C) and PET-CT (D). (To view
a color version of this image, please refer to the CD-ROM.) Reproduced with permission from Ciernik IF et al.6

biopsy results. It was felt that PET is excellent for the ini-
tial visualization of head and neck cancers and that 4 months
after RT is the best time to repeat scans to determine tumor
response (Figure 18.6-5).
Terhaard and colleagues evaluated 18FDG-PET in detect-
ing local recurrence in irradiated patients with laryngeal
and pharyngeal cancer.9 Of 75 patients studied, local recur-
rence was noted in 37 on the basis of biopsy findings. All
patients with recurrent tumor also had a positive 18FDG-
PET scan. The 18FDG-PET findings were positive in the first
set of scans in 34 of the 37 patients, for a sensitivity of 92%.
The positive predictive value (PPV) was 71% (34 of 48
patients). 18FDG-PET was then repeated in 27 patients (34
more scans). When scans were collectively analyzed, posi-
tive scans were found in 45 of 48 patients (94% sensitivity).
The PPV was 67% (45/67). False-positive results were attrib-
uted to extensive speaking or swallowing after 18FDG admin-
istration and to inflammation, radionecrosis, and edema.
The authors concluded that 18FDG-PET should be the first
diagnostic scan when local recurrence is suspected. If the
scan results are negative, no biopsy is required. However,
if the results are positive, a biopsy should be performed; if
the biopsy is negative and a follow-up scan shows decreased
18FDG uptake, local recurrence is unlikely (Figure 18.6-6).
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FIGURE 18.6-4. Upper three views of computed tomography–determined volume overlaid on lower three views of positron emission tomography
(PET) –determined volume. Interactive translations and rotations enable fusion of the two images. (To view a color version of this image, please refer
to the CD-ROM.) Reproduced with permission from Daisne JF et al.7

Rogers and colleagues studied the use of 18FDG-PET in
12 irradiated patients with stage III–IV head and neck can-
cer who underwent 18FDG-PET imaging before and 1
month after RT.10 A planned neck dissection and patho-
logic correlation with post-RT scans were performed. The
sensitivity, specificity, PPV, and negative predictive value
(NPV) of 18FDG-PET were 45%, 100%, 100%, and 14%,
respectively. These results suggest that whereas positive PET
findings after RT might accurately indicate the presence of
residual disease, negative PET scans after RT cannot be

FIGURE 18.6-5. A patient with head and neck cancer who underwent
pretreatment positron emission tomography (left), which was nega-
tive 1 month after radiotherapy (middle) and positive 4 months after
radiotherapy (right). Reproduced with permission from Greven KM et
al.8
FIGURE 18.6-6. Fluorodeoxyglucose–positron emission tomography
study obtained in a patient with glottic squamous cell carcinoma 19
months (left) and 30 months (right) after radiation therapy. Reproduced
with permission from Terhaard CH et al.9
 Functional Imaging in Head and Neck Cancer: Emerging Technology / 311
relied on to indicate absence of disease. More data are clear-
ly necessary before 18FDG-PET should be used as the sole
basis for deciding whether to omit post-RT neck surgery.
With the increasing use of hybrid scanners, 18FDG-PET
will likely have an increasing role in the planning of IMRT.
However, the two studies just described also demonstrate
the utility of 18FDG-PET in monitoring treatment response.
Radiolabeled Amino Acids
Although 18FDG is the most commonly used metabolic
imaging marker, radiolabeled amino acids have also been
studied. The advantages of amino acids over 18FDG in PET
include less uptake in inflammatory tissue and that the total
amino acid signal corresponds to the extent of tumor pro-
liferation.11
Leskinen-Kallio and colleagues studied the efficacy of
[11C]-methionine ([11C]-MET)–PET in head and neck
tumors.12 In 46 patients evaluated, tumors were visualized
by [11C]-MET–PET in 42 patients. In 3 patients, the tumor
was not well delineated owing to tracer accumulation in
adjacent structures. Only one tumor was not visualized.
These results suggest that [11C]-MET may be effective in
imaging malignant head and neck tumors. The disadvan-
tages of [11C]-MET include a short half-life and its ten-
dency to accumulate in the salivary glands.
Recently, de Boer and colleagues used L-[1-11C]-tyro-
sine (TYR)–PET to evaluate treatment response in 19 irra-
diated patients with laryngeal cancer.13 These patients
underwent a TYR-PET scan before RT (PET1) and at 3
months (PET2). Patients who had suspected recurrence on
physical examination then underwent a third TYR-PET
scan (PET3). If recurrence was suspected, CT and biopsy
were also performed. All 19 patients had a positive PET1
scan. Of 15 who agreed to have the PET2 scan, 7 had resid-
ual disease suspected on physical examination. Of these,
4 had a positive PET2 scan and 3 had a negative PET2 scan,
all of which were confirmed by histologic studies. The other
8 had no residual disease on physical examination; 1 had
a positive PET2 scan, and the remaining 7 had a negative
PET2 scan, with, again, all findings confirmed by histolog-
ic studies. The sensitivity, specificity, PPV, and NPV of
the PET2 were all 100%. Of 6 patients with a suspected
recurrence, 4 had a positive PET3 scan and 2 had a nega-
tive PET3 scan. These results were also verified by histo-
logic studies. Thus, for the PET3 scan, the sensitivity,
specificity, PPV, and NPV were all 100%. The results of this
small study suggest that TYR-PET is highly accurate in
determining the response to RT in laryngeal cancer.
However, larger studies are needed to further corroborate
these results and to determine whether TYR-PET is pre-
dictive in other tumor sites.
Other radiolabeled amino acids that remain to be tested
include L-3-iodo-a-methyltyrosine, O-(2-[18 F] fluoroethyl-
L-tyrosine, and [18F-α-methyl]-TYR. These two radioiso-
topes have longer half-lives than the two amino acids
described above. More studies of these markers are also
required to assess their predictive value in head and neck
cancer.
Radiolabeled Nucleosides
Radiolabeled nucleosides may also prove useful for meta-
bolic imaging for IMRT planning. This modality directly
assesses the synthesis of deoxyribonucleic acid (DNA).
Several of these radiopharmaceuticals have been studied.
[11C]-Thymidine and [methyl-11C]-thymidine have
been found to achieve high uptake in head and neck car-
cinomas.14 However, although [11C]-thymidine achieved
substantial uptake in patients in early studies, consistent-
ly high levels were not achieved in numerous patients.
Because of the 20-minute half-life of the [11C]-
thymidines, bromodeoxyuridine (BrdU), a thymidine ana-
log, is being used instead to label cells undergoing DNA
synthesis. BrdU has been labeled with 76Br for imaging
tumors in mice.15 More work needs to be done, however,
to make the uptake of this reagent more DNA specific.
High expression of thymidine phosphorylase has been
associated with decreased survival in patients with head and
neck cancer. An inhibitor of this enzyme, 5-chloro-6-(2-
iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione,
has been shown to shrink tumors in mice.16 This has
prompted the use of radiolabeled analogs of this inhibitor
to image tumors expressing the enzyme at high levels.
Commonly used isotopes in this setting are 125,131I and 211At.
Recently, Cobben and colleagues compared 18F-3´-fluoro-
3´-deoxy-L-thymidine (FLT) and FDG imaging of laryn-
geal cancer.17 In this study, 11 patients with suspected
recurrence and 10 with histologically confirmed primary
laryngeal cancer underwent biopsy after PET. Mean stan-
dardized uptake values (SUVs), maximum SUVs, and tumor
to nontumor (TNT) ratios were determined. Both modal-
ities correctly detected laryngeal cancer in 15 of 17 patients.
However, the uptake values were higher for FDG. Namely,
the maximum SUVs were 3.3 for 18FDG versus 1.6 for FLT.
Corresponding mean SUVs and TNT ratios were 2.7 ver-
sus 1.2 and 1.9 versus 1.5, respectively. In one patient, FLT-
PET showed only faint uptake of the marker, whereas
18FDG-PET showed intense uptake. FLT may thus not be
ideal for clinically detecting laryngeal cancer and for RT
treatment planning.
Although, to date, radiolabeled amino acids and nucleo-
sides have not been used for planning IMRT in head and neck
cancer, the future may see their use as alternatives to FDG.
Functional Imaging of Tumor Hypoxia
In 1955, Thomlinson and Gray first described the phe-
nomenon of tumor hypoxia.18 Over the next half-century,
researchers established that tumor hypoxia is associated
with radioresistance and hence the poor locoregional con-
trol of locally advanced cancers. This prompted efforts to
visualize tumor hypoxia in a noninvasive way.
312 / Intensity-Modulated Radiation Therapy
Iodinated azomycin arabinoside for SPECT and fluo-
romisonidazole for PET were among the first markers used
to image tumor hypoxia.19 Because of limitations in spatial
resolution, however, neither gained widespread acceptance.
In 1997, Fujibayashi and colleagues reported that Cu (II)
diacetyl-bis-(N4- methylthiosemicarbazone), or 60Cu-ATSM,
was selectively retained in ischemic myocardial tissue but
washed out of normoxic myocardium.20 Lewis and colleagues
confirmed this selective uptake in rat tumor models.21 The
partial pressure of oxygen in tissue was measured via a nee-
dle oxygen electrode. Some animals breathed 100% O2 to
mimic normoxic conditions; hydralazine was administered
in others to simulate hypoxic conditions. 60Cu-ATSM uptake
was increased by 37% in the rats administered hydralazine.
Chao and colleagues evaluated the feasibility of this non-
invasive hypoxia tumor marker in guiding head and neck
cancer IMRT planning.19 Specifically, a subvolume of hypox-
ic tumor within the GTV (hGTV) was determined using
60Cu-ATSM-PET. This image was then fused with a cor-
responding CT image, and an IMRT treatment plan was
generated. This process involved several steps.
First, the quality of the image fusion needed to be eval-
uated in terms of image integrity after transfer, spatial tar-
get alignment, image fusion accuracy, and system
functionality. A custom-made head phantom with CT and
PET visible targets was fabricated to determine the spatial
accuracy of target volume mapping (Figure 18.6-7). The
spatial accuracy was then confirmed after coregistration by
containing visible targets on the CT scans and checking
FIGURE 18.6-7. An anthropomorphic head phantom is used to confirm the accuracy of image registration and the fusion process. Plastic ampules,
serving as fiducial markers, were placed to help assess the accuracy of coregistration of computed tomography (CT) and positron emission tomog-
raphy (PET) images. Reproduced with permission from Chao KS et al.19
them on the PET image. These contours were within 2 mm
of each other on the two images.
Second, 60Cu-ATSM–PET and CT images were obtained
and fused. Patients underwent CT scanning wearing a ther-
moplastic immobilization head mask, with the markers
described above used to assist in image fusion. For PET scan-
ning, the patients were first injected intravenously with 13 mCi
of 60Cu-ATSM. Patients then underwent 60 minutes of dynam-
ic PET scanning in the thermoplastic masks. The respective
images were sent to an imaging workstation for image seg-
mentation and fusion using the AcQSim software (Philips
Medical Systems, Andover, MA) (Figures 18.6-8 and 18.6-9).
Third, target determination and delineation were per-
formed. GTV and clinical target volume (CTV) were demar-
cated per International Commission on Radiation Units
and Measurements reports 50 and 62.9,10 To subdelineate
the hGTV, tumor volumes shown by 60Cu-ATSM PET to
have a minimum threshold intensity were designated as
ATSM-avid. 60Cu-ATSM uptakes in normoxic muscle in
the contralateral neck were also examined, and this involved
the calculation of the average normoxic muscle intensity.
Volumes with a tumor to muscle (T:M) ratio of 2 or greater
were deemed hypoxic. No normal tissues in the neck exhib-
ited T:M ratios of 2 or greater. Thus, the volume within the
GTV with a T:M of 2 or greater was considered hypoxic.
After the volumes and subvolumes were demarcated, these
images were transferred to a planning computer to generate
IMRT plans (Figure 18.6-10). The dose prescription strate-
gy for hypoxia imaging-guided IMRT was modified. Dosing
 Functional Imaging in Head and Neck Cancer: Emerging Technology / 313

FIGURE 18.6-8. Computed tomography (CT)–positron emission tomography (PET) image fusion done using fiducial markers in a patient with squa-
mous cell carcinoma of the right tonsil and neck nodes. Reproduced with permission from Chao KS et al.19

FIGURE 18.6-9. Using the fused image shown in Figure 18.6-8, the hypoxic tumor fraction (hypoxic gross tumor volume [GTV]) is subdelineated with-
in the GTV. CT = computed tomography; 60Cu-ATSM = Cu (II) diacetyl-bis-(N4- methylthiosemicarbazone). (To view a color version of this image, please
refer to the CD-ROM.) Reproduced with permission from Chao KS et al.19
314 / Intensity-Modulated Radiation Therapy
FIGURE 18.6-10. Flow chart summarizing the overall process used to coor-
dinate hypoxia imaging-guided intensity-modulated radiation therapy
(IMRT). CT = computed tomography; Cu-ATSM = Cu (II) diacetyl-bis-(N4-
methylthiosemicarbazone); DICOM = Digital Imaging and Communication
in Medicine; GTV = gross tumor volume; hGTV = hypoxic gross tumor vol-
ume; PET = positron emission tomography; T/M = tumor to muscle.
Reproduced with permission from Chao KS et al.19
was as follows: 80 Gy in 35 fractions to the hGTV, 70 Gy in
35 fractions to the GTV, 60 Gy total to the CTV, and no more
than 30 Gy total to the parotid glands (Figure 18.6-11).
This study demonstrated the utility of hypoxia imaging-
guided IMRT. However, several issues remain. First, the dose
needed to overcome radioresistance owing to tumor hypoxia
FIGURE 18.6-11. Dose distribution of hypoxia imaging-guided intensity-modulated radiation therapy. The yellow line corresponds to 80 Gy, the green
line corresponds to 70 Gy, and the blue line corresponds to 50 Gy. (To view a color version of this image, please refer to the CD-ROM.) Reproduced
with permission from Chao KS et al.19
is unclear. The relationship between 60Cu-ATSM intensity
and radiocurability through the correlation of pathologic
and imaging findings needs to be more closely examined. In
addition, the tumor target uncertainty of the hGTV within
the GTV needs to be better ascertained. Last, we need to bet-
ter understand tumor reoxygenation kinetics.
Magnetic Resonance Imaging
MRI Fusion
MRI is very useful in target volume delineation. Emami and
colleagues evaluated eight patients with nasopharyngeal car-
cinoma who underwent CT with T1- and T2-weighted MRIs.22
Three treatment plans were generated: (1) a three-dimen-
sional conformal radiation therapy (3DCRT) plan based on
CT, (2) a 3DCRT plan based on fused CT and MRI targets,
and (3) an IMRT plan based on fused CT and MRI targets
(Figure 18.6-12). The first plan achieved adequate target cov-
erage and critical structure sparing. However, because MRI-
based targets were larger and more irregularly shaped, some
of the target might not have been incorporated. The second
plan led to underdosing of the GTV and the exposure of crit-
ical structures to increased doses. The last plan achieved both
better PTV coverage and critical structure sparing.
Quantitative Tissue Perfusion
Tissue perfusion can significantly affect tumor respon-
siveness to RT; thus, it is important to gauge perfusion to
improve treatment planning. A noninvasive MRI spin-
labeling technique has been studied to see if it could accu-
rately show tissue prefusion.23 Specifically, the long
relaxation time T1 was measured with segmented snapshot
fast low-angle shot (FLASH) imaging. Using a two-com-
partment tissue model, perfusion values were determined
pixelwise. Perfusion images with a slice thickness of 10 mm
and an in-plane resolution of 1.9 × 2.8 mm2 were acquired.
 Functional Imaging in Head and Neck Cancer: Emerging Technology / 315
FIGURE 18.6-12. Schematic demonstrating magnetic resonance and
computed tomography (CT) image fusion as part of three-dimensional
conformal radiation therapy and intensity-modulated radiation thera-
py treatment planning in nasopharyngeal carcinoma. CT = computed
tomography; CTV = clinical target volume; GTV = gross tumor volume;
MR = magnetic resonance imaging. Reproduced with permission from
Emami B et al.22
This spin-labeling technique visualizes tumor and normal
tissue perfusion plus changes in perfusion during RT.
However, the technique needs further refinement before it
can be used for IMRT planning (Figure 18.6-13).
Future Trends in Functional Imaging
Apoptosis Assessment
Apoptosis has recently been studied as a marker of tumor
response to chemotherapy24 and is also a major form of cell
death that occurs in response to RT. Researchers therefore
FIGURE 18.6-13. A patient with head and neck
carcinoma with right-sided lymph node neck
metastasis. (A) Fast low-angle shot (FLASH)
image before radiation therapy; enhanced per-
fusion values are observed at the edge of the
tumor, (D) (A) FLASH image obtained after 54 Gy
of treatment shows a moderate reduction in
the size of the tumor with high perfusion in the
center of the tumor (E); (C) and (f) show decreas-
es in areas of poor perfusion. (To view a color
version of this image, please refer to the CD-
ROM.) Reproduced with permission from
Schmitt P et al.23
needed to develop a technique to measure apoptosis and
recognized the annexin V–phosphatidylserine complex that
is expressed on the extracellular membrane when a cell
undergoes apoptosis as a potentially useful marker. One
resulting imaging method, technetium 99m (99mTc)-rh-
annexin V PET-SPECT, has been used as a way to measure
apoptosis in cancer patients undergoing chemotherapy.24
Currently, 99mTc-rh-annexin V uptakes in human tumor
after RT are also being studied.
Epidermal Growth Factor Receptor
Several studies have shown that the antagonism of growth
factor receptors may promote radiosensitivity. Most atten-
tion has focused on the epidermal growth factor (EGF)
pathway. The monoclonal antibody IMC-225, which blocks
ligand binding and inhibits autophosphorylation and down-
stream intracellular signaling, has been shown to improve
tumor response to RT.25
The in vivo visualization of the EGF receptor EGFR may
thus enable clinicians to determine which patients should
concurrently receive IMC-225. Several radiopharmaceuti-
cals have been tested for this purpose. A 99mTc-labeled anti-
EGF antibody has been shown to accurately gauge EGFR
expression both in tumor-bearing animal models and in
a patient with head and neck carcinoma.26 Other radioiso-
topes being tested include 123I-EGF and 111In–diethylen-
etriamine pentaacetic acid (DTPA)-EGF.27,28 However,
more studies need to be done before these drugs can be
used clinically.
Molecular Imaging and Radiobiologic Phenotyping
Several strategies are being developed that make use of mol-
ecular imaging and that may be useful in IMRT planning.
These strategies use nuclear magnetic resonance or nuclear
medicine techniques for the actual imaging.
316 / Intensity-Modulated Radiation Therapy
The first strategy is “indirect” or reporter gene imaging.
Hackman and colleagues29 and Blasberg and Gelovani30
transfected W256 tumor cells with adenovirus containing
the Escherichia coli cytosine deaminase (CD)–herpes sim-
plex virus type 1 thymidine kinase (HSV1-tk) fusion
(CD/TK) gene. Noninvasive imaging to monitor CD/TK
gene expression was performed with [124I]2´-fluoro-2´-
deoxy-1-β-D-arabinofuranosyl-5-iodouracil (FIAU)–PET.
HSV1-tk activity was monitored with [124I]-FIAU–PET,
and CD activity was determined by the CD enzyme assay.
[124I]-FIAU accumulation was found to be directly related
to CD/TK expression. CD enzyme activity was also direct-
ly related to CD/TK expression. Further, a significant lin-
ear relationship between [124I]-FIAU accumulation and
CD enzyme activity was observed. Thus, it was concluded
that individual elements of CD/TK gene expression can be
measured by noninvasive imaging, in particular [124I]-
FIAU–PET.
The second strategy is “direct” imaging of endogenous
molecules, such as cell surface receptors. An example of such
“direct” imaging involves the use of antisense ribonucleic
acid (RNA) targeting the messenger ribonucleic acid
(mRNA) of key oncogenes.31 This strategy entails the use
of radiolabeled oligonucleotides (RASONs), which are small
oligonucleotide sequences complementary to target mRNA
or DNA. RASON probes directly image gene expression at
the point of transcription. However, critical issues with
RASONs are generating a sufficient amount of antisense
RNA, stabilizing the antisense RNA, confirming the acces-
sibility of the binding domain, and ensuring sufficient
amounts of target mRNA.
The third strategy is “surrogate” or biomarker imag-
ing.30 Surrogate imaging is best defined as monitoring of
the downstream events that result from molecular-genetic
processes. This method may be useful in the development
of biochemical pathway–specific drugs. In particular, it may
be useful for monitoring the response to antiangiogenesis
treatment. However, a key drawback of the method is its
decreased specificity owing to the number of other mole-
cular-genetic processes.
These molecular imaging strategies are still very new,
and more work is needed to make them useful for the plan-
ning of different RT modalities.
Future Trends in Molecular Imaging
Many other novel approaches to molecular imaging that
may find application in RT planning and monitoring are
also being pursued. One method is to assess angiogenesis
by imaging the binding motif on integrin, a proangiogenic
factor that binds to numerous ligands in the extracellular
matrix. This binding motif is composed of –Arg-Gly-Asp-
(RGD). The imaging of cyclic RGD peptides, using 18F,
99mTc, and 111In, has been used to gauge angiogenesis.32
More studies of this approach are needed.
Another molecular imaging method uses as its basis P-
glycoprotein, the product of the multidrug-resistance gene
MDR1, which belongs to a group of energy-dependent
efflux transporters. Pgp is overexpressed in numerous
malignant tumors. The imaging of Pgp expression to pre-
dict resistance to both chemotherapy and RT has been
investigated using the myocardial perfusion agents 99mTc-
tetrofosmin and 99mTc-furifosmin (Figure 18.6-14).33
However, these SPECT agents need to be examined fur-
ther in clinical settings.
Conclusions
The field of radiation oncology is at a key crossroad.
Throughout the twentieth century, RT was planned based
on anatomic imaging. However, with the advent of IMRT
and functional imaging, the era of physical conformity is
coming to an end. We are now entering the era of biolog-
ic conformity.1 Biologic imaging, which includes imaging
tumor hypoxia, tumor proliferation, and tumor burden,
will enable radiation oncologists to define a “biologic tar-
get” volume. Use of the biologic target volume, in con-
junction with IMRT, can vastly enhance target delineation
and dose delivery. Such multidimensional RT may improve
the success of cancer treatment.
Similarly, Coleman has advocated a molecular approach
to RT. In this approach, radiation is viewed as an instiga-
tor of molecular events (Figure 18.6-15).34 In short, this
novel approach could enable scientists to study radiation’s
effects on molecular damage and molecular treatment.
Such molecular profiling could be performed before and
after RT and over time. Ultimately, the combination of
molecular and functional imaging with molecular profil-
ing and novel therapeutics holds great promise.
FIGURE 18.6-15. The changing view of radiation oncology as the insti-
gator of molecular events. Molecular profiling can be performed before
and after radiation therapy and after chemotherapy. Linac = linear accel-
erator; Rx = treatment. Reproduced with permission from Coleman CN.34
 Functional Imaging in Head and Neck Cancer: Emerging Technology / 317
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