[资料]PET-CT在勾画非小细胞肺癌的生物靶区中的作用

Implementing Biologic Target Volumes in
Radiation Treatment Planning for Non–Small
Cell Lung Cancer
Jeffrey D. Bradley, MD1,3; Carlos A. Perez, MD1,3; Farrokh Dehdashti, MD2,3; and Barry A. Siegel, MD2,3
1Department of Radiation Oncology, Mallinckrodt Institute of Radiology, St. Louis, Missouri; 2Department of Radiology,
Mallinckrodt Institute of Radiology, St. Louis, Missouri; and 3Alvin J. Siteman Cancer Center, Washington University
School of Medicine, St. Louis, Missouri
18F-FDG PET offers the radiation oncology community the ability
to incorporate biologic information into radiation therapy targets.
To date, most of the work in this arena has involved
patients with non–small cell lung cancer (NSCLC). The literature
suggests that biologic targeting with PET alters the radiation
treatment volume significantly in 30%–60% of NSCLC patients
for whom definitive therapy is planned. This is mostly the result
of the incorporation of regional nodes with 18F-FDG avidity that
were previously judged to be uninvolved by CT criteria. The
development of the integrated PET/CT scanner is a valuable
tool that improves diagnostic accuracy for staging this disease
and will increase the accessibility of PET for radiation treatment
planning. Its implementation into radiation treatment planning
requires strong collaboration between radiation oncologists and
nuclear physicians. In this report, we will review the literature on
PET-based radiation treatment planning, its potential benefits,
and future challenges.
Key Words: PET/CT; non–small cell lung cancer; radiation
therapy
J Nucl Med 2004; 45:96S–101S
In recent years, technologic advances in PET have created
increasing interest in the use of this modality for more
accurate tumor staging and treatment planning. The ability
to obtain information with PET regarding tumor biology has
led to the concept of biologic target volumes in radiation
treatment planning (RTP). Use of this biologic information,
in addition to the anatomic information obtained by CT or
MRI, offers a new opportunity to target cancers for radiation
therapy. Although the clinical application of PET has
largely been focused on its uses in differentiating benign
from malignant disease and for the staging of malignant
neoplasms, PET has great potential for RTP. To date, most
of this work has involved patients with non–small cell lung
cancer (NSCLC). The recent development of the integrated
PET/CT scanner promises to facilitate the application of
PET in patients receiving definitive radiation therapy for
cancer. In this paper, we review the literature on PET-based
RTP in NSCLC, its potential benefits, and future challenges.
BACKGROUND
At the present time, clinical oncologic PET is performed
almost exclusively with the radiolabeled glucose analog
2-[18F]-FDG. Compared with normal tissues, most tumors
have higher metabolic rates for glucose (and for 18F-FDG)
(1). 18F-FDG PET allows direct demonstration in vivo of
this fundamental biochemical disturbance associated with
malignant neoplasms. After injection, 18F-FDG is accumulated
intracellularly by membrane glucose transporter proteins
and then undergoes phosphorylation by hexokinase to
18F-FDG-6-phosphate (1). However, 18F-FDG-6-phosphate
is not further metabolized via glycolytic or glycogen-synthetic
pathways, and, because it is charged, cannot diffuse
out of cells that have absent or low activity of glucose-6-
phosphate. Therefore, 18F-FDG-6-phosphate becomes metabolically
“trapped” within the cell. The tissue level of 18F
radioactivity reflects the rate of glucose consumption at a
specific site.
RTP APPLICATIONS FOR LUNG CANCER
A large body of literature documents the value of PET in
the diagnosis and staging of NSCLC. About 10%–30% of
patients with stages I–III NSCLC as determined by conventional
imaging may be found with PET to have distant
metastases (2). An additional 10%–20% may be upstaged
by finding regional nodal involvement that was not previously
appreciated (3). As a result, 18F-FDG PET offers a
potential benefit in treatment planning for these patients
(Figs. 1 and 2).
Several investigators have reported results for staging the
mediastinal lymph nodes with 18F-FDG PET (4–14). In 1 of
the largest studies, Pieterman et al. (14) evaluated 102
patients with resectable NSCLC and compared the results of
Received Sep. 17, 2003; revision accepted Nov. 3, 2003.
For correspondence or reprints contact: Jeffrey D. Bradley, MD, Department
of Radiation Oncology, Washington University School of Medicine, 4921
Parkview Place, St. Louis, MO 63110.
E-mail: bradley@radonc.wustl.edu
96S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 45 • No. 1 (Suppl) • January 2004
PET and CT. The sensitivity and specificity of PET for
detection of mediastinal metastases were 91% and 86%,
respectively. The corresponding values for CT were 75%
and 66%, respectively (P
0.001). PET identified distant
metastases not detected by standard methods in 11 of the
102 patients. The use of PET resulted in lowering of the
clinical stage in 20 patients and upstaging in 42 patients
(4–14). Toloza et al. (15) recently reported a metaanalysis
of results comparing CT and PET staging of mediastinal
nodes. The pooled sensitivities were 57% and 84% for CT
and PET, respectively. The pooled specificities were 82%
and 89%, respectively. The sensitivity and specificity of
combined CT and PET interpretation ranged from 78% to
93% and from 82 to 95%, respectively. Thus, it is predictable
that the combination of PET with CT will provide an
improvement over CT alone for targeting radiation therapy.
Several studies have reported the effect of 18F-FDG PET
on radiation treatment volumes in bronchogenic carcinoma
(16–23) (Table 1). In most of these studies, the additional
information provided by PET has been incorporated through
FIGURE 1. Fused PET/CT images of patient
with T4 N2 M0, stage IIIB NSCLC.
Patient has 2 primary lesions in right lower
lobe (best seen in C) with adenopathy in
subcarinal (A) and right paratracheal regions
(B). PET and CT images were coregistered
with aid of fiducial markers, 1 of
which is shown in A. (D) Beam arrangement
used to cover biologic target volume.
FIGURE 2. PET/CT images of patient
with T2 N3 M0, stage IIIB NSCLC, showing
biologic target volume to include right upper
lobe lesion (A and C), ipsilateral cervical
adenopathy (B and D), and bulky subcarinal
adenopathy (D). Cervical adenopathy
was not appreciated on previous CT examination
of thorax but was detected with
PET.
PET/CT FOR RADIATION TREATMENT PLANNING • Bradley et al. 97S
side-by-side comparison of CT and PET images or by
digital overlays of separately obtained PET and CT data
(image fusion). In a retrospective study, Nestle et al. (18)
reported that incorporation of PET findings would have
altered the shape of the radiation portals in 12 of 34 patients
(35%). They used a qualitative visual method to determine
target volumes. Kiffer et al. (17) used a method of graphical
coregistration of coronal PET reconstructions overlaid on
fluoroscopic simulation films. They found inadequate coverage
of the tumor delineated on PET in 4 of 15 patients for
whom treatment was planned with CT alone. They also
reported an improved demarcation of tumors by PET in 3
additional patients with atelectasis. Use of the PET images
for planning would have altered the radiation therapy portals
in 7 of 15 patients (47%). Vanuytsel et al. (20) reported
a theoretic comparison of gross tumor volume (GTV) defined
by CT and by coregistered PET  CT. The pathologic
extent of nodal disease was mapped by cervical mediastinoscopy
in all patients. CT-based and PET  CT–based
nodal maps were compared. PET findings altered the theoretic
portal volume in 45 of 73 patients (62%).
Munley et al. (19) performed a retrospective study of
patients with lung cancer who underwent preirradiation
SPECT lung perfusion scintigraphy (n  104) and 18F-FDG
PET (n  35) in addition to the standard CT of the thorax
used to perform radiation therapy treatment planning. In the
35 patients in whom CT and PET data were used for
treatment planning, 12 (34%) had portions of the beam
aperture enlarged beyond the initial design based on the CT
scan alone. For the majority of these cases, the PET-defined
target volume encompassed the CT-defined target volume
so that the treatment planner had confidence that the difference
between the target volumes was not the result of a
coregistration error. Beam orientation based on the CTdefined
target was generally not changed by PET imaging
data.
MacManus et al. (24) reported on a prospective trial in
which diagnostic PET studies were used for RTP. Among
the 102 patients who underwent definitive irradiation, PET
led to a significant increase in the target volume in 22
because of inclusion of structures previously considered not
involved by tumor. In 16 patients the target volume was
significantly reduced, because PET demonstrated areas of
lung consolidation or enlarged lymph nodes with low 18FFDG
uptake that were excluded from the treatment volume.
In 3 patients, primary tumors were seen on PET that were
not identified on CT.
A few recent studies have used radiation therapy simulation
based on fusion of CT and 18F-FDG PET. Mah et al.
(25) performed RTP via coregistration of 18F-FDG and CT
images in 30 patients undergoing definitive radiation therapy
for NSCLC. Patients in this prospective study were
immobilized for radiation therapy simulation and imaged
using a coincidence -camera. Treatment was significantly
altered in 12 patients (40%). The treatment intent became
palliative in 7 patients. The target volume was altered to
include nodal disease detected by coincidence imaging in 5
patients. The treatment volumes based on CT were judged
to be inadequate in comparison with those based on combined
CT and 18F-FDG imaging in 17%–29% of the cases,
depending on the physician who contoured the volumes.
Giraud et al. (21) used -camera coincidence imaging of
18F-FDG fused with simulation CT images using external
fiducial markers. Significant alterations in treatment were
seen for 5 of the 11 patients (45%). Additional nodal disease
was detected in 4, and metastatic disease was detected in 1.
Erdi et al. (22) reported on 11 patients with NSCLC studied
with a dedicated PET scanner who underwent sequential CT
and PET simulations. The planning target volume (PTV)
increased in 7 of 11 patients (64%) to incorporate additional
regional nodal disease. PET also helped to differentiate
tumor from atelectasis in 2 patients. In summary, these
reported studies suggest a significant alteration in tumor
volume coverage in approximately 30%–60% of patients
with NSCLC whose treatment was planned using 18F-FDG
images (Table 1).
We have prospectively evaluated 26 patients with stages
I–III NSCLC referred for definitive radiation therapy or
chemoradiation therapy (J.D. Bradley et al., Int. J. Radiat.
Oncol. Biol. Phys., in press). All patients underwent CT
simulation for radiation therapy followed immediately by
18F-FDG PET. Each patient was accompanied to the PET
scanner by a trained radiation therapy technologist and
positioned using custom immobilization and external lasers.
External fiducial markers were used to fuse the 2 image
datasets for RTP. The CT alone and PET/CT coregistered
images for each patient were maintained separately. The
target volume contours were delineated by separate radiation
oncologists and compared. 18F-FDG PET findings altered
the American Joint Committee on Cancer TNM stage
in 8 of 26 patients (31%), and 2 patients who were diagnosed
with metastatic disease based on 18F-FDG PET re-
TABLE 1
Reports on Effect of FDG PET Imaging on Radiation
Treatment Volumes in Non–Small Cell Lung Cancer
Study authors Year
No. of
patients Method
Effect on
RTP*
Hebert et al. 1996 20 Visual 6
Hiffer et al. 1998 15 Visual 7
Nestle et al. 1999 34 Visual 12
Munley et al. 1999 35 Visual 12
Vanuystel et al. 2000 73 Image fusion 45
Giraud et al. 2001 12 Image fusion 5
Erdi et al. 2002 11 Image fusion 9
Bradley et al. 2003 24 Image fusion 14
*Number of patients whose radiation target volumes were either
substantially expanded to include additional tumor detected by PET
or reduced to exclude regions not involved on PET.
RTP  radiation treatment planning.
98S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 45 • No. 1 (Suppl) • January 2004
ceived palliative radiation therapy. Of the 24 patients whose
treatment was planned using 3-dimensional conformal radiation
therapy, PET significantly altered the radiation therapy
volume outlined in 14 (58%). PET helped to distinguish
tumor from atelectasis in 3 patients. Unsuspected nodal
disease was detected by PET in 10 patients. A separate
tumor focus within the same lobe of the lung was detected
in 1 patient. Our results are similar to those in other studies
described here.
FUTURE CHALLENGES
Although the incorporation of PET into RTP promises
substantial benefits, achieving this in routine clinical practice
poses several important challenges. These relate to the
interpretation of PET images, proper coregistration of PET
and CT images, computer software required for image transfer
to and acceptance by treatment planning systems, and
mechanisms to account for tumor motion. Most important is
the need to validate that this technology improves patient
outcomes.
PET Image Interpretation
Contoured target volumes are subject to interpretations
that vary among observers. In a report from Mah et al. (25),
3 radiation oncologists independently defined the GTV using
first CT data alone and then fused CT and 18F-FDG PET
images. Target definition with 18F-FDG PET varied, depending
on the physicians reading the studies, leading to a
reduction in PTV from 24% to 70% in some cases and an
increase from 30% to 76% in others. Radiation oncologists
are not trained to interpret PET images. Strong collaboration
is required between radiation oncology and nuclear
medicine specialists for proper interpretation of images. In
addition, reliable tools for tumor thresholding need to be
developed. PET images are usually interpreted qualitatively
in nuclear medicine but need to be interpreted quantitatively
in radiation oncology, where edge detection is required for
tumor contouring (Fig. 3).
Image Registration
Problems with image coregistration arise from differences
in patient positioning between routine PET acquisition
and radiation therapy delivery. Proper coregistration
requires identical patient set-up for both PET imaging and
radiation treatment. Patients receiving radiation therapy are
treated on a flat tabletop and are often immobilized using
custom body molds. A flat tabletop insert, transfer of patient
immobilization devices to the PET unit, and assurance that
these immobilization devices are properly applied all aid in
PET image acquisition for radiation oncology. Proper patient
alignment is aided by the use of external lasers (identical
to those in the simulator and radiation treatment rooms)
and by having a radiation therapist accompany the patient
to the PET facility to help with immobilization and positioning.
Coregistration of PET and CT images obtained with an
integrated PET/CT scanner leads to improved image interpretation.
Lardinois et al. (26) recently reported a prospective
study of 50 patients with suspected or proven NSCLC
and compared the accuracy of interpretations of CT alone,
PET alone, visually correlated PET and CT, and the combined
PET/CT data. Histopathologic staging was the reference
standard for both nodal and distant metastases. The
integrated PET/CT interpretations provided additional information
in comparison with interpretations based on visual
correlation of PET and CT in 20 of 49 patients. The
diagnostic accuracy was improved with the integrated study
for both tumor (P  0.001) and nodal (P  0.013) staging.
Thus, it is reasonable to expect that the information provided
by integrated PET/CT will increase the accuracy of
RTP in a similar manner. Although as yet no reports of
radiation treatment planning using the integrated PET/CT
unit have appeared in the literature, we and others have
begun to use such devices for the treatment planning process
in patients with NSCLC. The initial experience suggests
that we have significantly improved image coregistration.
However, inherent differences between PET and CT
data acquisition, especially with regard to respiratory motion,
have not been successfully addressed with current
PET/CT scanners. Fixing these deficiencies is an important
goal of current research in this area.
PET Image Accessibility
Accessibility of the images remains one of the main
difficulties for radiation oncology applications. For images
to be transferred and accepted, a common electronic language
is required. Most new PET/CT scanners export images
in Digital Imaging and Communications in Medicine
(DICOM) standard format. However, many older PET scanners
do not. Likewise, some RTP software systems do not
accept DICOM images. This problem is likely to be solved
with future software releases, but consumers should be
aware of these software requirements when considering
their own needs with regard to PET-based RTP.
FIGURE 3. PET images in patient with right hilar cancer. (A)
PET threshold is set at 40% of maximum standard uptake value
(SUV) of tumor. (B) PET threshold is set at 30% of maximum
SUV. If delineating this tumor using PET alone, different threshold
settings would result in different target volumes.
PET/CT FOR RADIATION TREATMENT PLANNING • Bradley et al. 99S
Tumor Motion
Tumor motion secondary to ventilation is problematic for
RTP of lung cancer, especially for lesions residing in the
lower lobes. Four-dimensional (4D) imaging has demonstrated
that these lesions may move up to 3 cm in a single
dimension and that such lesions typically move in trajectories
involving each of the x, y, and z coordinates (27–29).
For RTP, 3 principal methods are used to account for tumor
excursion. The first is to fuse CT images obtained at endtidal
inspiration and end-tidal expiration to obtain a composite
tumor volume within the limits of tidal breathing (4D
method) (29). The second method is to gate the linear
accelerator to “beam on” during specific phases of the
ventilatory cycle when the tumor is within the radiation
therapy portal (gating method). The third method is to gate
the patient by breath hold maneuvers by an active breath
control device (ABC) or with deep inspiration breath hold
(DIBH) (30–33). Each of these methods has its advantages
and disadvantages with respect to radiation treatment delivery.
The 4D method is simple to implement but enlarges the
radiation treatment volume, which leads to increased normal
tissue doses. The gating method is available via hardand
software from vendors and is currently being implemented
in some clinics with either stereotactic radiotherapy
or intensity modulated radiation therapy expertise. The
ABC and DIBH techniques may be of limited use in the
lung cancer population with compromised lung function.
The incorporation of PET into RTP will affect each
method of radiation therapy. The addition of PET simplifies
the 4D volume method. Whereas spiral CT scanning takes
seconds (and is performed with breath holding), PET imaging
takes several minutes. Thus, the PET tumor volume
itself provides the composite 4D volume that accounts for
tumor excursion. Implementation of the gating method using
PET/CT–based RTP would require gated PET images.
Thus, in addition to the technologic requirements for gating
the linear accelerator, an institution would need a mechanism
to gate the PET acquisition. This method has an
advantage in yielding smaller radiation therapy volumes and
lower radiation dose to normal tissues, but its implementation
will require intensive research and development. Investigators
at Memorial-Sloan Kettering Cancer Center have
developed a camera-based respiratory gating system to link
each phase of the respiratory trace with PET images acquired
during that phase of the respiratory cycle (34).
Will Biologic Target Volumes Affect Patient Outcome?
Finally, we need to demonstrate whether the use of PET
in RTP will improve patient outcome beyond the information
gained with diagnostic PET. Mac Manus et al. (24)
have reported on a prospective study demonstrating that
diagnostic PET studies obtained for staging are predictive of
outcome. In the study, 153 patients with unresectable
NSCLC who were candidates for radical radiation therapy
underwent PET imaging after conventional staging. Distant
metastases were detected by PET in 28 patients (18%) in the
lung, extrathoracic lymph nodes, bone, adrenal, liver and
other abdominal sites, and skin. In several patients, multiple
metastatic sites were detected. Extensive regional nodal
disease was detected in 18 (12%). After PET, 107 patients
(70%) were judged to be potentially eligible for curative
treatment: radiation therapy with concurrent platinum chemotherapy
in 68, radiation therapy alone in 34, and definitive
surgery in 5 patients. The 5 surgical patients had been
considered inoperable before PET was performed. In the
remaining 46 patients (30%), palliative therapy was given
after PET. Patients treated with definitive treatment had a
significantly better 2-y survival (44%) than those treated for
palliation (0%). With both CT and PET staging, about 75%
of patients with stage I NSCLC survived 2 y in contrast to
45% of those with stage II and III disease. There were no
2-y survivors with stage IV disease. Additional prospective
trials are needed to demonstrate the impact of PET-based
RTP on patient outcomes. The Radiation Therapy Oncology
Group is developing a limited-institution pilot study for
patients with stages I–III NSCLC for whom radiation therapy
is planned using information from integrated PET/CT
scanners. This small study has been difficult to initiate
because of PET image transfer issues described previously.
The answer to the question of whether improvements in
outcome can be achieved awaits future studies.
Potential Applications for Other Radiopharmaceuticals
Imaging with 18F-FDG represents only a first step in the
application of PET in oncology. Other radiopharmaceuticals
that interrogate molecular targets other than glucose transporter
proteins and hexokinase can provide important information
about tumor biology that also should be exploitable
for RTP. One such example is Cu(II)-diacetyl-bis-N-(4)-
methylthiosemicarbazone (Cu-ATSM), which can be labeled
with several positron-emitting radionuclides of copper.
PET with Cu-ATSM reliably identifies regions of
hypoxia within tumor. We have previously shown that tumor-
to-muscle ratios on Cu-ATSM PET in patients with
NSCLC are predictive of response to radiation therapy (35).
These more radioresistant volumes of tumor can potentially
be selectively targeted with higher doses of radiation. The
development of intensity-modulated radiation therapy, a
tool to deliver radiation doses more conformally, can potentially
be used to target these hypoxic regions and thus to
deliver heterogeneously designed radiation doses (36). Another
example is 3-deoxy-3-[18F]fluorothymidine (FLT),
which assesses tumor cell proliferation (37,38). FLT is
taken up by cells and phosphorylated by thymidine kinase 1.
FLT-monophosphate is trapped within the cell, and its concentration
provides a measure of cellular thymidine kinase
activity, which reflects the rate of cell proliferation. Knowledge
of patient-specific tumor proliferation rates may conceptually
aid in selecting patients for altered fractionation
schedules. The development of innovative radiopharmaceuticals
will continue to provide opportunities for the exploitation
of biologic targets.
100S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 45 • No. 1 (Suppl) • January 2004
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