Comparison of Changes in Tumor Metabolic
Activity and Tumor Size During Chemotherapy
of Adenocarcinomas of the Esophagogastric
Hinrich A. Wieder, MD1; Ambros J. Beer, MD2; Florian Lordick, MD3,4; Katja Ott, MD4; Michael Fischer, MD2;
Ernst J. Rummeny, MD2; Sibylle Ziegler, PhD1; Jo ¨rg R. Siewer, MD4; Markus Schwaiger, MD1;
and Wolfgang A. Weber, MD1
1Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universita ¨t Mu ¨nchen, Munich, Germany;2Department of
Radiology, Klinikum Rechts der Isar, Technische Universita ¨t Mu ¨nchen, Munich, Germany;3Department of Hematology and
Oncology, Klinikum Rechts der Isar, Technische Universita ¨t Mu ¨nchen, Munich, Germany; and4Department of Surgery,
Klinikum Rechts der Isar, Technische Universita ¨t Mu ¨nchen, Munich, Germany
We evaluated the temporal relationship between chemother-
apy-induced changes in tumor glucose use and tumor size.
Methods: Twenty patients with adenocarcinoma of the esopha-
gogastric junction (AEG) were studied by18F-FDG PET and CT
scans before neoadjuvant chemotherapy, 14 d after the initia-
tion of therapy, and 4 wk after the completion of therapy.
Results: The relative change in18F-FDG uptake was more than
2 times larger than the decrease in tumor size at all time points
(P ? 0.01). At 14 d after the initiation of chemotherapy, there
was no correlation between the reduction in18F-FDG uptake
and tumor wall thickness. The change in18F-FDG uptake after
14 d of therapy was significantly correlated with the reduction in
tumor size after the completion of therapy. Conclusion: In AEG,
changes in tumor metabolism are a more sensitive parameter
for assessing the effects of chemotherapy than are changes in
tumor size. Early changes in metabolic activity predict the sub-
sequent reduction in tumor size.
Key Words: CT;
J Nucl Med 2005; 46:2029–2034
18F-FDG PET; esophageal cancer; therapy
In the treatment of locally advanced adenocarcinoma of
the esophagogastric junction (AEG), neoadjuvant chemo-
therapy can improve the outcome of patients who respond to
preoperative therapy compared with surgical treatment
alone. However, the prognosis for patients who do not
respond to preoperative therapy seems to be even worse
than that for patients treated by surgery alone (1–4). Initial
reports have indicated that effective chemotherapy causes a
rapid decrease in tumor
cancer and AEG and that18F-FDG PET can differentiate
between eventually responding and nonresponding tumors
within 2 wk after the initiation of chemotherapy and after
the end of chemotherapy (5–8). It is a common assumption
that morphologic imaging techniques can assess changes in
tumor size not before 8–12 wk of chemotherapy. However,
to our knowledge the time course of changes in tumor size
during chemotherapy has not been systematically studied so
far. Therefore, it is not clear whether metabolic changes
actually precede the reduction in tumor size. Knowledge
about changes in tumor size during chemotherapy is also of
importance for the interpretation of18F-FDG PET scans
because part of the measured reduction of tracer uptake
during chemotherapy could be caused by a reduction in
tumor size resulting in an underestimation of the true18F-
FDG uptake because of partial-volume effects (9). The
goals of this study were therefore to evaluate the time
course of tumor metabolic activity measured by18F-FDG
PET and tumor size measured by multislice CT (MSCT)
and to analyze whether there is a correlation between early
changes in18F-FDG uptake and changes in tumor size.
18F-FDG uptake in esophageal
MATERIALS AND METHODS
PET and CT scans for 20 consecutive patients who underwent
PET and CT for assessment of tumor response as part of phase II
studies evaluating neoadjuvant chemotherapy of AEG were ana-
lyzed in this study. The sample size of 20 patients was based on the
following power calculation. In a previous study, we had observed
that18F-FDG uptake of AEGs decreased by 31% ? 27% (mean ?
SD) within 2 wk after the initiation of chemotherapy (7). The
present study was designed to detect with 80% power that the
decrease in tumor18F-FDG uptake was at least 20 percentage
Received May 7, 2005; revision accepted Aug. 19, 2005.
For correspondence or reprints contact: Hinrich A. Wieder, MD, Depart-
ment of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universita ¨t
Mu ¨nchen, Ismaninger Strasse 22, 81675 Munich, Germany.
PET AND CT IN ESOPHAGEAL CANCER • Wieder et al.
points larger than the change in tumor diameter. Under these
assumptions, 20 patients are needed to detect this difference in a
paired t test at a significance level of P ? 0.05. Sample size
calculations were performed with the PS program (10). In the first
phase II study from which patients were recruited (n ? 10), all
patients underwent 2 cycles of preoperative chemotherapy. In the
second study (n ? 10), treatment was changed on the basis of the
findings of the18F-FDG PET scan (11). Patients with a decrease in
tumor18F-FDG uptake of at least 35% after 2 wk of chemotherapy
(metabolic responders) underwent 2 full courses of chemotherapy.
In contrast, chemotherapy was stopped and the tumor was resected
in metabolic nonresponders (?35% decrease in18F-FDG uptake).
In both studies, inclusion criteria consisted of the presence of
biopsy-proven adenocarcinoma of the distal esophagus (AEG I) or
cardia (AEG II), with or without local lymph node metastases and
without distant metastases (tumor stage T3 NX M0 or T4 NX M0)
(7). Patients were treated with 2 cycles of platinum-based combi-
nation chemotherapy (each with a duration of 36 d) as described
previously (7). The study protocol was approved by the Ethics
Committee of the University of Technology, Munich, Germany,
and written informed consent was obtained from every patient.
Patient characteristics are summarized in Table 1.
An18F-FDG PET scan was performed for each patient before
the initiation of preoperative chemotherapy and 14 d after the
initiation of chemotherapy. In 14 patients, a third PET scan 3–4
wk after the completion of chemotherapy (13–14 wk after the
initiation of chemotherapy, immediately before surgery) was per-
Patients fasted for at least 6 h before PET to minimize blood
glucose and insulin levels and to ensure standardized metabolism
in all patients. Blood glucose levels were measured before each
PET examination. All measured values were less than 150 mg/dL
and showed no significant changes during chemotherapy. Static
emission images (20 min) of the tumor region were acquired 40
min after intravenous injection of 300–370 MBq of18F-FDG by
use of an ECAT EXACT PET scanner (CTI/Siemens). After the
emission scan, transmission measurements were performed for
attenuation correction. Images were reconstructed iteratively with
an attenuation-weighted ordered-subset expectation maximization
algorithm (8 iterations, 4 subsets) and then smoothed in 3 dimen-
sions with a 4-mm gaussian filter. Quantitative image analysis was
performed by 1 specialist in nuclear medicine who had more than
2 y of experience in PET imaging and who was not provided with
clinical information concerning the patients.
Circular regions of interest (ROIs) with a diameter of 1.5 cm
(corresponding to 10 pixels) were manually placed over the tumor
at the site of maximum18F-FDG uptake in the baseline scan. In the
following PET scans, the ROIs were placed in the same positions
as in the baseline study. Standardized uptake values (SUVs) nor-
malized to patient body weight were calculated from the average
activity values in the ROIs. On the basis of previously described
criteria (12), patients were excluded if tumor18F-FDG uptake was
too low for quantitative analysis. The length of the tumor in
coronal slices was measured by 1 observer. For these measure-
ments, the images were scaled to the maximum18F-FDG uptake of
the tumor tissue and displayed on a computer screen by use of an
inverted gray scale. With these standardized display settings, the
Patient Characteristics and Changes in Tumor Wall Thickness and in Tumor18F-FDG Uptake
Tumor18F-FDG uptake (SUV)
Tumor wall thickness (mm)
Baseline After 2 wkPreopBaseline After 2 wkPreop
Mean ? SD 59 ? 8.77.7 ? 3.6 4.8 ? 2.03.0 ? 0.9 20 ? 1019 ? 9 14 ? 5
*Four women and 15 men.
Preop ? preoperative; NA ? not applicable.
THE JOURNAL OF NUCLEAR MEDICINE • Vol. 46 • No. 12 • December 2005
extent of the tumor was determined visually. Measurements were
performed on a Sun Workstation (Sun Microsystems) running
ECAT 7.1 software (CTI/Siemens).
For all patients, MSCT was performed before the initiation of
preoperative chemotherapy, 14–17 d after the initiation of chemo-
therapy, and directly before surgical resection (13–14 wk after the
initiation of chemotherapy, 3–4 wk after the completion of che-
Patient preparation included the oral administration of 500 mL
of water directly before the scan, followed by an injection of 40 mg
of N-butylscopolamine intravenously to dilate the esophagus and
stomach. After intravenous administration of 120–150 mL of
iodine contrast agent (Imeron 300; Altana) at a flow rate of 3 mL/s,
a VolumeZoom Scanner (Siemens) was used to perform a CT scan
of the thorax and upper abdomen in the late arterial enhancement
phase (delay of 30 s) and then a scan of the abdomen in the portal
venous phase. The following scan parameters were used: tube
voltage, 120 kV; tube current, 180 mAs; collimation, 4 ? 1 mm;
slice thickness, 1.25 mm; and reconstruction increment, 0.8 mm.
Images were sent to a Leonardo Workstation (Siemens) for further
analysis. The maximum wall thickness was measured in the axial
plane at the same height for each examination; the maximum
length of the tumor was measured in the coronal reconstructed
images. Images were analyzed by 1 resident in radiology who had
more than 2 y of experience in CT and who was unaware of any
clinical information concerning the patients as well as the results
of the18F-FDG PET scan. For measurement of the size of the
tumor, a soft-tissue window was used to display the CT images on
the computer screen (center, 50 Hounsfield units; width, 350
Hounsfield units). Tumor extent was assessed visually by taking
into account the regional wall thickness of the esophagus as well
as contrast enhancement. Measurements were performed on the
Leonardo Workstation with standard Syngo Software tools (Sie-
Statistical analyses were performed with the StatView program
(SAS Institute Inc.). Quantitative values were expressed as
mean ? 1 SE (SEM) or mean ? 1 SD. Intra- and interindividual
comparisons of absolute values and changes in tumor18F-FDG
uptake and tumor wall thickness were performed with Wilcoxon
signed rank or paired t tests and Mann–Whitney tests, respectively.
Correlations between quantitative parameters were evaluated by
linear regression analysis. All statistical tests were performed at
the 5% level of statistical significance.
Time Course of18F-FDG Uptake, Tumor Length, and
Tumor Wall Thickness
One tumor showed only low
baseline examination in comparison to the surrounding tis-
sue (SUV, 3.7) and therefore was excluded from further
analysis. All other tumors (n ? 19) showed intense18F-FDG
uptake, with a mean SUV at baseline of 7.7 (SD, 3.6). At
14 d after the initiation of chemotherapy, the SUV de-
creased significantly to 4.8 (SD, 2.0) (relative change,
?35%; SD, 16%; P ? 0.01) (Fig. 1). At the preoperative
scan (13–14 wk after the initiation of chemotherapy, di-
18F-FDG uptake at the
rectly before surgery), there was a further significant de-
crease in the SUV to 3.0 (SD, 0.9) (relative change, ?53%;
SD, 21%; n ? 14; P ? 0.01 for a comparison with the
baseline scan and the first follow-up scan) (Fig. 1). Maxi-
mum tumor SUVs showed similar changes during therapy.
The maximum SUVs at the time of the first, second, and
third PET scans were 8.8 (SD, 3.9), 5.3 (SD, 2.2), and 3.6
(SD, 1.1), respectively. The corresponding relative changes
were ?38% (SD, 18%; from the first scan to the second
scan) and ?55% (SD, 23%; from the first scan to the third
scan). Therefore, only the mean SUVs were used for further
The mean tumor length in18F-FDG PET at baseline was
64 mm (SD, 19). At 14 d after the initiation of chemother-
apy, the length decreased significantly to 57 mm (SD, 19
mm) (relative change, ?9%; SD, 10%; P ? 0.01). After the
completion of chemotherapy, the tumor length in18F-FDG
PET decreased further to 41 mm (SD, 10) (relative change,
?34%; SD, 20%; P ? 0.01 for a comparison with the length
at the time of the second PET scan).
The mean tumor wall thickness at baseline was 20 mm
(SD, 10). At 14–17 d after the initiation of chemotherapy,
the mean wall thickness was 19 mm (SD, 9) (relative
change, ?4%; SD, 20%; P ? 0.23) (Fig. 1). After the
completion of chemotherapy, the mean tumor wall thick-
ness decreased significantly to 14 mm (SD, 5) (relative
change, ?26%; SD, 27%; P ? 0.0075) (Fig. 1). The mean
tumor length in CT was 85 mm (SD, 18) at baseline and
showed no significant decease at 14–17 d after the initiation
of chemotherapy (84 mm; SD, 20) (relative change, ?1%;
SD, 6%; P ? 0.6). At the preoperative scan, there was a
significant decrease in the mean tumor length to 71 mm
(SD, 23) (relative change, ?16%; SD, 16%; P ? 0.01).
and tumor wall thickness. Error bars denote 1 SEM.
Time course of changes in tumor18F-FDG uptake
PET AND CT IN ESOPHAGEAL CANCER • Wieder et al.
The relative decrease in the SUV at 14 d after the initi-
ation of chemotherapy and after the end of chemotherapy
was significantly higher than the corresponding decrease in
tumor wall thickness (P ? 0.01, as determined by paired t
tests or Wilcoxon tests) (Fig. 1). Figure 2 shows an example
of a tumor with a marked decrease in18F-FDG uptake after
2 wk of therapy but no apparent change in size.
Correlation Among18F-FDG Uptake, Tumor Length,
and Tumor Wall Thickness
At 14 d after the initiation of chemotherapy, there was no
correlation between the reduction in the SUV and changes
in tumor wall thickness (r2? 0.16, P ? 0.05) (Fig. 3A) or
tumor length (r2? 0.08, P ? 0.5). Similarly, there was no
correlation between changes in tumor length as measured by
PET and CT (P ? 0.5). In contrast, there was a significant
correlation between early changes in tumor18F-FDG uptake
and the reduction in tumor size after the completion of
therapy (r2? 0.38, P ? 0.005) (Fig. 3B). Changes in tumor
length after 2 wk of therapy showed no significant correla-
tion with the reduction in tumor wall thickness after the
completion of therapy (r2? 0.18, P ? 0.05).
Metabolic changes at 2 wk after the initiation of chemo-
therapy also were significantly correlated with the reduction
in metabolic activity after the completion of therapy (r2?
0.63, P ? 0.0007) (Fig. 4A). In contrast, early changes in
tumor wall thickness (r2? 0.20, P ? 0.05) (Fig. 4B) or
length (r2? 0.005, P ? 0.35) did not predict a reduction in
tumor size after the completion of therapy.
This study demonstrates that chemotherapy causes a de-
crease in tumor18F-FDG uptake that precedes a reduction in
tumor size. Tumor18F-FDG uptake decreased significantly
by 35% at 2 wk after the initiation of chemotherapy; at the
same time, there was only a minimal decrease in tumor wall
thickness as measured by MSCT. Furthermore, the decrease
in tumor18F-FDG uptake at 2 wk after the initiation of
therapy was significantly correlated with a reduction in
tumor size after the completion of chemotherapy, indicating
that early quantitative metabolic changes predicted subse-
quent morphologic tumor responses. In contrast, measure-
ments of tumor size by CT and tumor length by CT and PET
after 2 wk of therapy were not significantly correlated with
a reduction in tumor size after the completion of therapy.
It is generally assumed that a reduction in tumor meta-
bolic activity precedes morphologic changes in tumor tis-
sue. However, very few data in the literature actually con-
firm this hypothesis. Wahl et al. (13) reported for 11 patients
with breast cancer that changes in18F-FDG uptake during
chemohormonotherapy were not accompanied by a decrease
in tumor size as measured by conventional mammography.
To our knowledge, no systematic studies have compared
changes in18F-FDG uptake with measurements of tumor
size by MSCT. Changes in tumor size early in the course of
treatment could significantly affect the measurement of ac-
tivity concentrations by PET. In this situation, the measured
activity concentrations would become smaller because of
(arrow) was almost unchanged in MSCT after 14 d of therapy but showed significant decrease after completion of therapy.
However,18F-FDG uptake by tumor after 14 d of therapy showed distinct decrease and was reduced to background levels in scan
MSCT and18F-FDG PET in patient before chemotherapy (CTx), after 14 d of therapy, and before surgery. Tumor size
THE JOURNAL OF NUCLEAR MEDICINE • Vol. 46 • No. 12 • December 2005
partial-volume effects, even if the true activity concentra-
tions were unchanged. Thus, the effect of treatment on
tumor metabolism would be overestimated by PET imaging.
Kessler et al. (14) and Brix et al. (15) developed a model for
calculating recovery coefficients (RCs) for spheres of vari-
ous diameters. This model is similar to the design of our
study, because most esophageal tumors have a long cranio-
caudal extension compared with their diameter and, in a first
approximation, resemble cylinders. For a cylinder with a
diameter of 20 mm (the mean tumor wall thickness before
therapy in the present study), a ratio between the concen-
tration of the cylinder and the concentration of the back-
ground of 4.0 (corresponding to the ratio of the tumor SUV
to the background SUV in the present study), and a spatial
resolution of the reconstructed images of 12 mm, the RC
was 90%. Under the same conditions, the RC for a 19-mm
cylinder (corresponding to the mean tumor wall thickness
after 14 d of therapy) was 88%. Although there were some
variations in wall thickness changes on a per-patient basis
(Table 1), most patients had only minor reductions in tumor
wall thickness. The average RCs at the baseline and at the
first and second follow-up scans were 84% (SD, 13%), 80%
(SD, 13%), and 70% (SD, 15%), respectively. Therefore, it
can be concluded that partial-volume effects cannot explain
the 35% decrease in18F-FDG uptake after 2 wk of therapy.
This conclusion is further corroborated by the lack of cor-
relation between changes in18F-FDG uptake and tumor wall
thickness (r2? 0.16).
The following limitations of this study should be noted.
Because of the small number of patients included in this
Correlation between early changes in18F-FDG uptake and early (A) and late (B) changes in tumor size.
changes in tumor metabolism. (B) Correlation between early and late changes in tumor size.
Relationship between early and late changes in tumor metabolism and size. (A) Correlation between early and late
PET AND CT IN ESOPHAGEAL CANCER • Wieder et al.
study, no attempt was made to calculate the sensitivity and Download full-text
specificity of18F-FDG uptake or CT for the prediction of a
histopathologic response (only 3 patients were histopatho-
logically classified as responders in this study). Only wall
thickness and length, not the volume of the tumor, were
measured in this study. Detailed volumetric measurements
may provide a more sensitive way to assess tumor response
by CT. However, accurate techniques for measuring tumor
volume in AEGs have not been established so far.
This study demonstrates that metabolic changes during
chemotherapy actually precede a significant reduction in
tumor size. This finding supports the concept that quantita-
tive assessment of tumor metabolism by18F-FDG PET is a
more sensitive test for monitoring tumor response than are
size measurements with anatomic imaging modalities.
We acknowledge the efforts of the cyclotron and radio-
chemistry staff at our institution. We appreciate the excel-
lent technical support of the technologists at our institution.
We thank Jeffrey Fessler, PhD, University of Michigan, for
generously providing the software for the iterative recon-
struction of the PET studies.
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