Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone).
ABSTRACT Tumor hypoxia indicates a poor prognosis. This study was undertaken to confirm our prior pilot results showing that pretreatment tumor hypoxia demonstrated by PET with (60)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) is a biomarker of poor prognosis in patients with cervical cancer. Thirty-eight women with biopsy-proved cervical cancer underwent (60)Cu-ATSM PET before the initiation of radiotherapy and chemotherapy. (60)Cu-ATSM uptake was evaluated semiquantitatively as the tumor-to-muscle activity ratio (T/M). A log-rank test was used to determine the cutoff uptake value that was strongly predictive of prognosis. All patients also underwent clinical PET with (18)F-FDG before the institution of therapy. The PET results were correlated with clinical follow-up. Tumor (60)Cu-ATSM uptake was inversely related to progression-free survival and cause-specific survival (P = 0.006 and P = 0.04, respectively, as determined by the log-rank test). We found that a T/M threshold of 3.5 best discriminated patients likely to develop a recurrence from those unlikely to develop a recurrence; the 3-y progression-free survival of patients with normoxic tumors (as defined by T/M of < or = 3.5) was 71%, and that of patients with hypoxic tumors (T/M of > 3.5) was 28% (P = 0.01). Tumor (18)F-FDG uptake did not correlate with (60)Cu-ATSM uptake, and there was no significant difference in tumor (18)F-FDG uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.9). Pretherapy (60)Cu-ATSM PET provides clinically relevant information about tumor oxygenation that is predictive of outcome in patients with cervical cancer.
- SourceAvailable from: Andreas Kjaer[Show abstract] [Hide abstract]
ABSTRACT: Background Hypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[18¿F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl-bis(N4)-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models.Methods Positron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and 64Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients.ResultsComparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. 64Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions.Conclusion Radiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, 64Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that 64Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning.Radiation Oncology 10/2014; 9(1):228. · 2.36 Impact Factor
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ABSTRACT: Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia.American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(6):490-506. · 3.25 Impact Factor
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ABSTRACT: In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed.World journal of clinical oncology. 12/2014; 5(5):824-844.
Assessing Tumor Hypoxia in Cervical
Cancer by PET with60Cu-Labeled
Farrokh Dehdashti1,2, Perry W. Grigsby2,4, Jason S. Lewis2,3, Richard Laforest1,3, Barry A. Siegel1,2, and
Michael J. Welch2,3
1Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, St. Louis, Missouri;2Siteman Cancer Center, Washington
University School of Medicine, St. Louis, Missouri;3Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology,
St. Louis, Missouri; and4Department of Radiation Oncology, Edward Mallinckrodt Institute of Radiology, St. Louis, Missouri
taken to confirm our prior pilot results showing that pretreatment
tumor hypoxia demonstrated by PET with60Cu-labeled diacetyl-
bis(N4-methylthiosemicarbazone) (60Cu-ATSM) is a biomarker of
poor prognosis in patients with cervical cancer. Thirty-eight
women with biopsy-proved cervical cancer underwent60Cu-
ATSM PET before the initiation of radiotherapy and chemother-
apy.60Cu-ATSM uptake was evaluated semiquantitatively as
the tumor-to-muscle activity ratio (T/M). A log-rank test was
used to determine the cutoff uptake value that was strongly pre-
dictiveof prognosis. Allpatients also underwent clinical PET with
18F-FDG before the institution of therapy. The PET results were
correlated with clinical follow-up. Tumor60Cu-ATSM uptake was
inversely related to progression-free survival and cause-specific
survival (P 5 0.006 and P 5 0.04, respectively, as determined by
the log-rank test). We found that a T/M threshold of 3.5 best dis-
criminated patients likely to develop a recurrence from those un-
likely to develop a recurrence; the 3-y progression-free survival
of patients with normoxic tumors (as defined by T/M of #3.5)
was 71%, and that of patients with hypoxic tumors (T/M of .3.5)
was 28% (P 5 0.01). Tumor18F-FDG uptake did not correlate
with60Cu-ATSM uptake, and there was no significant difference in
tumor18F-FDG uptake between patients with hypoxic tumors and
those with normoxic tumors (P 5 0.9). Pretherapy60Cu-ATSM
PET provides clinically relevant information about tumor oxygena-
tion that is predictive of outcome in patients with cervical cancer.
Key Words: PET;60Cu-ATSM; hypoxia; cervical cancer; survival
J Nucl Med 2008; 49:201–205
Tumor hypoxia has been shown to be important in deter-
mining the response to therapy in solid tumors, includ-
ing cervical cancer. Hypoxic cells are more resistant to
killing by ionizing radiation and chemotherapy, more likely
to be locally invasive and to metastasize, more resistant
to apoptosis, and more genetically unstable (1,2). Thus,
because of the importance of tumor hypoxia, considerable
research has focused on developing methods to measure
hypoxiareliably aswellasonstrategiesfor improvingtumor
oxygenation or ameliorating the effects of hypoxia. Consid-
ering the new therapeutic agents that target hypoxia, identi-
fying a practical method for detecting hypoxia becomes
highly important. In general, a method suitable for routine
clinical application needs to be practical, readily available,
and reliable. Polarographic oxygen electrodes (Eppendorf
GmbH) made it possible to measure tumor oxygenation,
which producedclinically relevantinformation.Early clinical
onstrated that hypoxic tumors, including cervical tumors,
respond poorly to radiation therapy (3–10). However, the
oxygen electrode method is invasive, technically demanding,
useful only for studying tumors accessible to electrode place-
ment, and subject to sampling errors. Thus, this method is not
considered clinically practical.
Recently, noninvasive imaging methods, particularly PET,
have received substantial attention. Several hypoxic tracers
zone) (60Cu-ATSM) (11).
60Cu-ATSM has rapid blood
clearance and is rapidly reduced and retained in hypoxic
tissues with a highhypoxic/normoxic tissue activity ratio (12).
We recently reported our preliminary results using60Cu-
ATSM PET in patients with cervical cancer (13). We dem-
onstrated that60Cu-ATSMuptakewas predictiveofprognosis
in patients with locally advanced cervical cancer. The present
group of patients.
MATERIALS AND METHODS
We prospectively studied 38 patients (23–84 y old) who had
biopsy-proved cervical cancer and who underwent PET with
Received Oct. 23, 2007; revision accepted Nov. 19, 2007.
For correspondence or reprints contact: Farrokh Dehdashti, MD, Edward
Mallinckrodt Institute of Radiology, 510 South Kingshighway Blvd., St. Louis,
COPYRIGHT ª 2008 by the Society of Nuclear Medicine, Inc.
jnm048520-pe n 1/8/08
ASSESSING TUMOR HYPOXIA BY PET • Dehdashti et al. 201
Journal of Nuclear Medicine, published on January 16, 2008 as doi:10.2967/jnumed.107.048520
60Cu-ATSM before the initiation of therapy. The results for 14 of
these patients included in our pilot study were reported previously
(13). This investigation was approved by the Human Studies
Committee and the Radioactive Drug Research Committee of
Washington University School of Medicine and by the Protocol
Washington University School of Medicine. All patients gave
informed consent before participating in the study.
(smoking history was not recorded), a physical examination, routine
laboratory studies (all patients had hemoglobin levels measured, and
these averaged 11.9 6 2.4 [mean 6 SD] g/dL before therapy),
body PET with18F-FDG, performed as part of our clinical routine.
treatment policies at the EdwardMallinckrodt Institute of Radiology
(14,15). All patients received external irradiation and intracavitary
weekly for 6 cycles) was given to 35 patients; the remaining 3 pa-
tient did not receive chemotherapy (because of severe comorbidity).
Clinical follow-up was performed 6 wk after the completion of
radiotherapy, at 3-mo intervals for the next 2 y, and then every 6 mo
thereafter. Standard criteria were used to evaluate the response to
therapy (14,15). The duration of follow-up for patients alive at the
time of the last evaluation ranged from 3 to 79 mo. Progression-free
survival and cause-specific survival were measured from the date
of completion of irradiation to the date of recurrence or death.
60Cu (half-life 5 0.395 h, b positron decay 5 92.5%, electron
capture 5 7.5%) was produced in the Cyclotron Corp. CS15
previously described procedures (16).60Cu-ATSM was produced
according to previously described methods (17). In brief,60CuCl2was
buffered with 1 M sodium acetate, 15 mg of H2ATSM (in dimethyl
60Cu-ATSM–containing solution was transferred to a preconditioned
C18SepPak Light cartridge (Millipore Corp.), which was washed
with water, and then the final60Cu-ATSM was eluted from the
cartridge in 0.1-mL fractions of ethanol. The fractions containing the
peak amounts of activity were combined, and the ethanol fraction was
and isotonic60Cu-ATSM solution had greater than 98% radiochemical
purity at the time of injection.
PET with60Cu-ATSM was performed with an ECAT HR1
scanner (Siemens-CTI). The performance specifications of this
scanner were previously reported (18); the scanner has a spatial
resolution of 4.5 mm full width at half maximum (FWHM).
The imaging level was determined by centering the tumor in the
scanner field of view by use of positioning lasers and by reference to
anatomic landmarks (e.g., pubic symphysis) seen on the CT study
or the clinical18F-FDG PET study. After the completion of a 10- to
15-min transmission scan, approximately 481 MBq of60Cu-ATSM
were injected intravenously. All patients then underwent a 60-min
reconstructed by filtered backprojection with measured attenuation
factors from the transmission scans. A postreconstruction gaussian
filter of 5 mm FWHM was used, corresponding to a final spatial
olution attributable to the positron range for60Cu.
For qualitative analysis, the60Cu-ATSM PET images were first
The images were then evaluated in correlation with the CTand18F-
assessed semiquantitatively by determining the tumor-to-muscle ac-
tivity ratio (T/M) from the summed images obtained at 30-60 min
after injection. This time interval was based on our previous studies
of patients with non–small cell lung cancer (NSCLC) and cervical
cancer; those studies demonstrated that semiquantitative analysis of
the summed data obtained at 30–60 min after injection provides
information similar to that achieved with a more formal quantitative
analysis of the images (13,19). In addition, this time interval rep-
resented a practical trade-off between image contrast and image
noise, considering the short half-life of60Cu-ATSM.
Clinical18F-FDG PET images were evaluated qualitatively with
In addition,18F-FDG uptake in the primary tumor was assessed
semiquantitatively by determination of the maximum standardized
uptake value (SUVmax) in the primary tumor.
To assess whether the tumor uptake of either60Cu-ATSM or18F-
FDG is predictive of the response to treatment, the PET results were
correlated with the results of clinical follow-up. The physician who
assessed the patients for disease progression was unaware of the
results of the60Cu-ATSM studies. The Kaplan–Meier method was
used to assess the relationship between60Cu-ATSM uptake and both
survival curves was tested with log-rank (Mantel–Cox) statistics. A
log-rank test was used to determine the cutoff uptake value that was
strongly predictive of prognosis. The relationships between60Cu-
ATSM uptake in the primary tumor and the presence of metastatic
and stage of disease were assessed by use of the Fisher exact and x2
statistics, respectively. The correlation between the tumor uptake of
60Cu-ATSMand thatof18F-FDG was evaluatedby linear regression.
All patients had locally advanced cervical cancer with
primary lesions of .2.0 cm in diameter (International
Federation of Gynecology and Obstetrics clinical stage Ib1
in 3 patients, stage Ib2 in 3 patients, stage IIa in 1 patient,
stage IIb in 18 patients, IIa in 1 patient, IIIb in 11 patients,
and IVa in 1 patient). Histologic analysis revealed the tu-
mors to be squamous cell carcinomas in 37 patients and an
adenosquamous carcinoma in 1 patient.
All patients underwent clinical
studies demonstrated markedly increased18F-FDG uptake
in the primary cervical tumors of all patients. The SUVmax
for the primary tumors was 11.5 6 6.7 (mean 6 SD). The
uptake of60Cu-ATSM in the cervical cancers was variable.
The tumor of one patient had no discernible60Cu-ATSM
uptake. The tumors of the remaining 37 patients had mea-
surable uptake of60Cu-ATSM. The T/M of60Cu-ATSM in
all patients was 3.8 6 2.0 (mean 6 SD).
18F-FDG PET. These
202THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 2 • February 2008
jnm048520-pe n 1/8/08
Thepatients were monitored for periods ranging from 3 to
were alive for periods ranging from 3 to 84 mo (median 5
41 mo), 24 with no evidence of cervical cancer and 3 with
a recurrence of cervical cancer. The remaining 11 patients
had died, 10 from recurrent cervical cancer and 1 from
intercurrent disease). Using log-rank analysis of our pre-
viously reported data, we found that a T/M threshold of 3.5
was a statistically significant cutoff value that accurately
distinguished patients whose cancer did not recur from those
who developed a recurrence after completing therapy. In the
present study, this cutoff value appeared to have similar
discriminatory power. The Kaplan–Meier survival estimates
for patients with T/M values above and below 3.5 are shown
inFigure 1. Progression-free survival and cause-specific
survival were significantly better in patients with a T/M
for60Cu-ATSM of #3.5 (P 5 0.006 and P 5 0.04, re-
spectively). The 3-y progression-free survival of patients
with normoxic tumors (T/M of #3.5) was 71%, and that of
patients with hypoxic tumors (T/M of .3.5) was 28% (P 5
0.01). The corresponding cause-specific survival estimates
were 74% and 49%, respectively (P 5 0.05). There was no
significant difference in the frequency of lymph node
involvement between patients with a T/M of .3.5 (9/16;
56%) and patients with a T/M of #3.5 (9/22; 41%) (P 5
0.6). Also, there was no significant correlation between
disease stage and tumor60Cu-ATSM uptake (P 5 0.46).
There was no significant difference in total radiation dose
(P 5 0.22) or overall treatment time (P 5 0.98) between
patients with a T/M of .3.5 and patients with
#3.5. Figures 2 and 3 show examples of hypoxic and
There was no significant correlation between the tumor
SUVmaxfor18F-FDG and the tumor uptake of60Cu-ATSM
(R25 0.006, P 5 0.63). The tumor uptake of18F-FDG in
hypoxic tumors was 11.7 6 4.2 (mean 6 SD), and that in
normoxic tumors was 11.5 6 8.4 (P 5 0.9, as determined
by an unpaired t test).
a T/M of
Hypoxia has been known to be a characteristic feature of
solid tumors and to play a crucial role in determining the
response to therapy and tumor progression (1). Therefore,
several therapeutic strategies have been developed to over-
come hypoxia or its effects, either by eliminating the hypoxic
state (e.g., blood transfusions or hyperbaric oxygenation) or
by sensitizing hypoxic cells to radiation with hypoxic cell
sensitizers (e.g., misonidazole). For these treatments to be
successful, the ability to identify hypoxia before therapy and
to monitor hypoxia during therapy with a clinically practical
method would be quite important. Such a method could
serve as a tool to improve and optimize patient care.
Direct measurement of tumor oxygenation was not possi-
in the 1980s. Clinical data obtained with oxygen electrodes
demonstrated the clinical relevance of tumor hypoxia (7,
20,21). These clinical studies demonstrated that tumor oxy-
genation is predictive of the response to therapy and the
treatment outcome (21–24). However, this method is inva-
sive, difficult to use, and unable to address tumor hetero-
geneity, which is an important feature of solid tumors; thus,
this method is not considered to be practical for routine
clinical use. Imaging, as a noninvasive method, has attracted
much attention. Imaging with hypoxic markers has the
ability to evaluate the entire tumor and thus is less prone to
sampling errors. Additionally, imaging allows for serial
assessment of the tumor during therapy and can demonstrate
the effects of therapy on the hypoxic regions of the tumor.
Among the different types of imaging, PET with various
hypoxic radiotracers has garnered the most attention.
2-propanol; FMISO) is the most widely studied agent for
which uptake is dependent on tissue oxygen levels and that
(right) of pelvis shows intense18F-FDG uptake in known primary
cervicalcancer. Sagittal60Cu-ATSM PET image coregisteredwith
CT image (left) at same level also demonstrates intense uptake in
primary cervical cancer (T/M 5 4.5). Note that there are different
patterns of18F-FDG uptake and60Cu-ATSM uptake in primary
tumor (P). B 5 urinary bladder.
Hypoxic tumor. Sagittal18F-FDG PET/CT image
(right) of pelvis shows intense18F-FDG uptake in known primary
cervicalcancer. Sagittal60Cu-ATSM PET image coregisteredwith
CT image (left) at same level demonstrates only mildly increased
uptake of this tracer in primary cervical cancer (T/M 5 3.0). As in
Figure 2, there are different patterns of18F-FDG uptake and60Cu-
ATSM uptake in primary tumor (P). B 5 urinary bladder.
Normoxic tumor. Sagittal18F-FDG PET/CT image
survival (right) determined from60Cu-ATSM uptake by Kaplan–
Meier method. s 5 event in patients with T/M of #3.5; , 5
event in patients with T/M of .3.5.
Progression-free survival (left) and cause-specific
ASSESSING TUMOR HYPOXIA BY PET • Dehdashti et al.203
jnm048520-pe n 1/8/08
has been used for hypoxia imaging in cancer patients.
FMISO accumulates in oxygen-deprived viable cells (25).
The first clinical studies to image hypoxia by PETwere done
with FMISO. Padhani et al. reported changes in FMISO
uptake with therapy (25). Eschmann et al. demonstrated
that high FMISO uptake at 4 h after injection was highly
associated with an incomplete response to curative radio-
therapy in patients with head and neck cancers or NSCLC
(26). For patients with head and neck cancers, Rischin et al.
showed that the risk of local recurrence was significantly
higher in patients with hypoxic tumors (27). However, the
pharmacokinetics of FMISO, which result in only modest
target-to-background ratios, have limited its routine clinical
use. In addition, urinary excretion of this tracer interferes
with the imaging of pelvic organs located near the urinary
However,60Cu-ATSM, a more recently developed PET
tracer, holds exceptional promise for the imaging of hyp-
oxic regions in tumors. The mechanism of retention of
60Cu-ATSM in hypoxic tissues is largely attributed to low
oxygen tension and the subsequent altered redox environ-
ment (increased nicotinamide adenine dinucleotide levels)
(11). Several in vivo and in vitro animal studies have shown
that60Cu-ATSM accumulates selectively in hypoxic cells,
clears rapidly from the blood, and washes out rapidly from
normoxic cells (11). One of the important properties of this
tracer is its minimal excretion by the urinary tract, which
makes it ideal for the evaluation of pelvic organs. In small
prospective clinical studies, we found that pretreatment
tumor60Cu-ATSM uptake was predictive of the response
in NSCLC and was predictive of both the response to
neoadjuvant chemoradiotherapy and survival in patients
with rectal cancer (19,28). We previously reported, for 14
patients with cervical cancer, that60Cu-ATSM uptake was
predictive of prognosis (13). We now report our expanded
experience for 38 patients with cervical cancer. We
confirmed the results of our earlier report and found that
tumor60Cu-ATSM uptake, as measured by T/M, allows for
the reliable discrimination of patients with a high likelihood
of early relapse from those with a low likelihood of early
relapse. As in our earlier report, we found that the T/M
cutoff value of 3.5 was reliable for predicting progression-
free and cause-specific survival in this group of patients.
Patients with hypoxic tumors (T/M of .3.5) had signifi-
cantly shorter progression-free and cause-specific survival
times than did those with normoxic tumors (T/M of #3.5)
(P 5 0.006 and P 5 0.04, respectively).
18F-FDG PET has been successfully used for the imaging
of oncology patients. The magnitude of18F-FDG uptake
has been shown to be an important prognostic factor inde-
pendent of established prognostic factors in patients with
tumors such as lung cancer and breast cancer (29,30).
Preclinical studies of human tumor cell lines and clinical
data suggest that hypoxia plays a role in tumor18F-FDG
uptake (31–35). It has been shown that hypoxia increases
the level of hypoxia-inducible factor 1a, which increases
the expression of glycolytic enzymes and glucose transport
proteins (36). However, many other factors affect18F-FDG
uptake in tumors; thus,18F-FDG is not a specific marker of
hypoxia. Double-tracer autoradiography with64Cu-ATSM
and18F-FDG and immunohistochemical staining of pro-
liferating cells (Ki67), blood vessels (CD34 or von
Willebrand factor), and apoptotic cells in 4 different
implanted tumor models in mice demonstrated that regions
64Cu-ATSM uptake were hypovascular and
consisted of tumor cells arrested in the cell cycle, whereas
regions with high18F-FDG uptake were hypervascular and
consisted of proliferating cells (37). Rajendran et al. studied
patients with head and neck cancers, soft-tissue sarcoma,
breast cancer, or glioblastoma multiforme and found that
the correlation between the overall tumor18F-FDG uptake
and the hypoxic volume (as measured with FMISO) was
small (Spearman r 5 0.24), with highly significant differ-
ences among the different tumor types (35). Thus,18F-FDG
uptake, which might indicate the presence of hypoxia,
should not be considered a surrogate marker for hypoxia.
Although hypoxic tracers map the hypoxic regions of
tumors, several studies have compared the uptake of18F-
FDG and FMISO or60Cu-ATSM and have demonstrated
that these tracers provide different types of information
about tumors (38,39). We found no significant correlation
between60Cu-ATSM and18F-FDG in patients with cervical
cancer, a finding similar to our findings for patients with
rectal cancer and NSCLC (19,28). No significant difference
in18F-FDG uptake by tumors defined as normoxic on the
basis of60Cu-ATSM uptake and those defined as hypoxic
was noted. Thus, our results also support the notion that the
prognostic information derived from
cannot be derived from18F-FDG PET.
One of the limitations of60Cu-ATSM for widespread clin-
ical use is related to its short radioactive half-life (0.40 h).
However, another radionuclide of copper,64Cu, has a much
longer half-life (12.7 h) and provides superior image quality
in comparison with60Cu. Several companies, such as MDS
Nordion, ACOM, Trace Life Sciences, and IsoTrace, are
now supplying64Cu for use in the labeling of radiophar-
maceuticals, such as64Cu-ATSM (40). With the increasing
availability of64Cu, it is likely that larger clinical trials
with64Cu-ATSM will be initiated in several regions of the
Pretherapy information on the oxygenation status of
a tumor could play an important role in treatment selection.
We have demonstrated that imaging with60Cu-ATSM PET
is a promising method for the assessment of tumor hypoxia
and has the potential to be clinically useful in the care of
patients with cancer. We confirmed our earlier results
showing that the uptake of60Cu-ATSM correlates well with
patient survival for patients with cervical cancer. Although
such information can be obtained with the oxygen electrode
method, imaging offers several important advantages, includ-
ing the ability to perform repeated, noninvasive assessments
of hypoxia in the entire tumor regardless of the location of
204THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 2 • February 2008
jnm048520-pe n 1/8/08
the tumor. This method can be used to identify patients for
clinical trials of treatment strategies designed to overcome
The authors greatly appreciate the technical support
provided by Linda Becker, Jennifer Frye, and Helen
Kaemmerer. We also acknowledge Tom F. Voller, Lucie
Tang, Todd A. Perkins, Dr. Rajendra Singh, Sally W.
Schwarz, and the cyclotron staff at Washington University
School of Medicine for their valuable assistance in the
production of60Cu. This work was supported by NIH Grant
CA81525 and DOE Grant DE-FG02-87ER60512.
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