DOI:10.2214/AJR.07.2126
AJR 2007; 189:1199-1202
© American Roentgen Ray Society
A Pilot Study of Early 18F-FDG PET to Evaluate the Effectiveness of Radiofrequency Ablation of Liver Metastases
Amir H. Khandani1,2,
Benjamin F. Calvo2,3,
Bert H. O'Neil2,4,
Jennifer Jorgenson1,5 and
Matthew A. Mauro2,5
1 Section of Nuclear Medicine, Department of Radiology, UNC School of Medicine,
CB #7510, Chapel Hill, NC 27599-7510.
2 UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC.
3 Division of Surgical Oncology, Department of Surgery, UNC School of Medicine,
Chapel Hill, NC.
4 Division of Hematology–Oncology, Department of Medicine, UNC School of
Medicine, Chapel Hill, NC.
5 Section of Vascular and Interventional Radiology, Department of Radiology, UNC
School of Medicine, Chapel Hill, NC.
Received February 26, 2007;
accepted after revision May 25, 2007.
Address correspondence to A. H. Khandani
(khandani{at}med.unc.edu).
Abstract
OBJECTIVE. The objective of our study was to collect pilot data
about the use of FDG PET within hours after radiofrequency ablation (RFA) of
liver metastases.
CONCLUSION. Total photopenia on early PET can potentially be
regarded as a macroscopic tumor-free margin; focal uptake can be regarded as
macroscopic residual tumor.
Keywords: FDG PET • liver cancer • liver metastasis • metastases • oncologic imaging • radiofrequency ablation
Introduction
Fluorine-18 FDG PET has been successfully used to monitor the effect of
chemotherapy—that is, to determine a patient's long-term outcome during
the ongoing treatment or shortly after its completion
[1]. Expanding the use of PET
to monitor the effect of other therapies, such as radiofrequency ablation
(RFA), would be of great benefit. RFA has been increasingly used for the local
treatment of liver metastases. The objective of local therapy is complete
ablation of the tumor along with a surrounding margin of normal tissue.
Complete surgical resection of liver metastases is confirmed by pathologic
examination of the specimen margins during the operation or immediately after
the surgery. If the goal of RFA is to duplicate the success rate of hepatic
resection, then tests are needed to confirm complete ablation within hours
after RFA. No noninvasive methods are currently available to assess for
complete tumor ablation in the period immediately after RFA. Capillaries
around the ablation site are particularly leaky in the weeks to months after
RFA, limiting the ability of IV contrast CT or MRI to reliably differentiate
between periablational hemorrhage and residual tumor during this period
[2]. Therefore, CT and MRI are
usually performed no sooner than 1 month after RFA. In practice, residual
disease is usually detected several months after RFA, at which time patients
most often undergo a second ablation procedure or chemotherapy.
Ablated liver cells lose the ability to take up 18F-FDG; thus,
complete ablation is visualized as an area of photopenia. Based on the
assumption that FDG uptake in inflammatory cell infiltrates causes
false-positive findings, PET has not been used to monitor the effect of
invasive procedures such as RFA. Laboratory animal data indicate that RFA does
not cause significant accumulation of inflammatory cells in the liver. Antoch
et al. [3] found photopenia
without any inflammatory uptake on PET or inflammatory cell accumulation on
histology within 90 minutes after RFA in pig liver. Tsuda et al.
[4] described neutrophils and
fibroblasts 3 days after RFA at the ablation site in rabbit liver. They
reported that 4 weeks after RFA the number of reactive cells had decreased and
that 12 weeks after RFA a thickened fibrous tissue with a few chronic
inflammatory cells was present. McGahan et al.
[5] described accumulation of
granulation tissue and polymorphonuclear cell infiltration at the ablation
sites in the swine liver 1 week after RFA; by week 5, they found that there
was moderately thickened fibrotic tissue with a few nests of chronic
inflammatory cells. In humans, Donckier et al.
[6] compared FDG PET and CT in
28 liver metastases (17 patients) at 1 week, 1 month, and 3 months after RFA
and found that FDG PET is superior to CT in detecting residual tumor. In
particular, PET performed 1 week after RFA indicated the existence of residual
disease, which was visualized as focal uptake at the ablation site, that was
confirmed by histology (n = 3) or long-term imaging follow-up
(n = 1). Although Donckier et al. did not specifically discuss the
subject of inflammatory uptake after RFA, there were no false-positive PET
findings. Similar results have been reported by Langenhoff et al.
[7] and Anderson et al.
[8].
Based on these previously reported data, FDG PET is used by many groups
such as ours to assess for residual tumor at the RFA site in the weeks and
months after the ablation. However, sparse data are available about the value
of using FDG PET in humans during the hours after RFA. Veit et al.
[9] retrospectively evaluated
15 liver metastases in 11 patients who had undergone FDG PET within 2 days
after RFA. On post-RFA PET, five lesions had inflammatory uptake that may have
obscured residual tumor; residual tumor was diagnosed at the ablation sites of
these five metastases on follow-up PET scans. The four patients with these
five metastases had undergone PET "later within the 2-day time range
rather on the first day after RFA"; the exact time points of PET in the
patients studied were not given. The authors questioned whether this
rim-shaped uptake, caused by "tissue regeneration," may have
obscured a minimal amount of residual disease. As those authors suggested,
these retrospective data warrant a prospective study of PET performed directly
after RFA.
The purpose of our prospective study was to show that 18F-FDG
PET can be used to evaluate the RFA site for macroscopic residual tumor within
hours after ablation, a scan that we have termed "early PET." Our
hypothesis was that false-positive findings related to inflammation would not
be observed at a very early time point so that any residual focal uptake would
likely be gross residual tumor.
Subjects and Methods
This study was approved by the institutional review board, and written
informed consent was obtained from all subjects. Eight sequential patients
(six men, two women) undergoing RFA as part of clinical management between
July 2005 and August 2006, each for a single liver metastasis (five colorectal
cancers, one malignant melanoma, one breast cancer, and one gastric carcinoid)
were studied. In four patients (patients 1, 4, 6, and 7), histologic proof of
metastatic disease in the ablated lesion was obtained before RFA. In the
remaining four patients, metastatic disease was assumed on the basis of a
histologic diagnosis of metastatic disease in other liver lesions, imaging
characteristics of the target lesion, or serologic markers.
The ablated lesions measured 1.5–4.2 cm on CT or MRI performed within
8 weeks before RFA, and all were hypermetabolic on PET performed within 4
weeks before RFA (pre-RFA PET). None of the subjects received chemotherapy
between pre-RFA PET and the ablation procedure. Study subjects underwent
18F-FDG PET (early PET) 2–41 hours after RFA.
In terms of treatment type, four patients underwent percutaneous RFA, and
four had surgically guided RFA (laparoscopy in two and laparotomy in two at
the time of partial hepatectomy of other hepatic metastases). Two patients who
underwent percutaneous RFA and were planned to be released from the hospital
on the same day were injected with 18F-FDG while in the observation
area and were brought to the PET suite immediately before the start of the
scanning. In the surgical cases, early PET was performed as soon as the
postoperative pain was tolerable to the patient such that the patient could
lie on the scanning table for the duration of the scan, approximately 12
minutes. The two patients having laparoscopic RFA underwent early PET on the
first postoperative day (19 and 20 hours after RFA), and the two patients with
laparotomic RFA underwent early PET on the second postoperative day (40 and 41
hours after RFA).
All subjects fasted before undergoing PET and did not receive any IV
glucose 6 hours before 18F-FDG injection. A standard dose of 444
MBq (12 mCi) of 18F-FDG was injected IV, and imaging was started 1
hour after injection. PET/CT scans from the upper abdomen, the so-called
"liver view," were obtained on a single-detector PET/CT unit
(Biograph, Siemens Medical Solutions) with an acquisition time of 6 minutes,
instead of the usual 3 minutes, per table position. We increased the
acquisition time with the intention of potentially improving sensitivity for
detecting small residual tumors after RFA
[10]. The total acquisition
time was about 12 minutes (two table positions), and the examination was well
tolerated by all subjects.
CT was performed while the patient took shallow breaths, and no IV or oral
contrast material was used. The images were reconstructed in three planes with
iterative reconstruction using the ordered subset expectation maximization
(OSEM) with two iterations and eight subsets. The spatial resolution of the
reconstructed images was 6.3-mm full-width at half-maximum. The transmission
CT scan was obtained with 130-kV tube voltage and 115-mAs tube current. The CT
images were reconstructed at a slice thickness of 5.0 mm to match the PET
images.
The images were reviewed prospectively by a nuclear medicine physician with
more than 5 years of experience interpreting PET. Total photopenia, focal
uptake, and rim-shaped uptake were regarded as complete ablation, residual
tumor, and inflammation, respectively. Standard uptake value (SUV) was not
used to quantify uptake at the ablation site; the size of any residual tissue
was expected to be in the subcentimeter range and, therefore, would have been
underestimated by the SUV because of partial volume effect. Patients underwent
follow-up 18F-FDG PET for 3–16 months after RFA as part of
clinical management. Findings on follow-up PET scans served as the reference
standard.
Results
Patient findings are summarized in Table
1. In brief, five patients (patients 1, 2, 4, 6 [Fig.
1A,
1B,
1C,
1D,
1E], and 8) had findings of
total photopenia at the ablation site on the early PET scan. In four of these
patients, total photopenia at the ablation site was seen on the follow-up PET
scans (follow-up times: 3, 6, 9, and 16 months after RFA), whereas
18F-FDG PET performed 8 months after RFA showed a round focus at
the ablation site in one patient (patient 2). That focus was larger and more
intense on subsequent PET scans; these findings are compatible with
microscopic residual tumor at the time of ablation. Two MRI scans and a CT
scan obtained within 5 months after RFA showed post-RFA changes at the
ablation site. Finally, an MRI scan obtained on the same day as the PET scan
was conclusive for residual tumor at the ablation site.
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TABLE 1: Characteristics of the Subjects Who Underwent Radiofrequency Ablation
(RFA) of Hepatic Metastases and of the Ablated Metastases
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Fig. 1A —72-year-old man with solitary metastasis to liver from ocular
malignant melanoma (patient 6 in Table
1). Fluorine-18 FDG PET scan obtained at outside institution
before radiofrequency ablation (RFA) shows intense metastasis
(arrowhead).
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Fig. 1B —72-year-old man with solitary metastasis to liver from ocular
malignant melanoma (patient 6 in Table
1). Early 18F-FDG PET scan obtained 19 hours after
laparoscopic RFA reveals total photopenia at RFA site (arrowhead),
which is compatible with complete ablation.
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Fig. 1C —72-year-old man with solitary metastasis to liver from ocular
malignant melanoma (patient 6 in Table
1). Follow-up 18F-FDG PET scans obtained 3 (C),
6 (D), and 9 (E) months after RFA show total photopenia
(arrowheads), thus confirming finding in B.
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Fig. 1D —72-year-old man with solitary metastasis to liver from ocular
malignant melanoma (patient 6 in Table
1). Follow-up 18F-FDG PET scans obtained 3 (C),
6 (D), and 9 (E) months after RFA show total photopenia
(arrowheads), thus confirming finding in B.
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Fig. 1E —72-year-old man with solitary metastasis to liver from ocular
malignant melanoma (patient 6 in Table
1). Follow-up 18F-FDG PET scans obtained 3 (C),
6 (D), and 9 (E) months after RFA show total photopenia
(arrowheads), thus confirming finding in B.
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Two patients (patients 5 and 7 [Fig.
2A,
2B,
2C]) had focal uptake at the
ablation site on the early PET scan. Both of these foci increased in size and
intensity on the subsequent PET scans, which is compatible with macroscopic
residual tumor at the time of ablation.
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Fig. 2B —66-year-old man with solitary metastasis to liver from
colorectal cancer (patient 7 in Table
1). Early 18F-FDG PET scan obtained 16 hours after
percutaneous RFA reveals focal uptake at RFA site (arrowhead), which
is compatible with residual tumor.
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Fig. 2C —66-year-old man with solitary metastasis to liver from
colorectal cancer (patient 7 in Table
1). Follow-up 18F-FDG PET scan obtained 5 months after
RFA show increased focal uptake at RFA site (arrowhead), thus
confirming finding in B.
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Only one patient (patient 3) had rim-shaped uptake on the early PET scan.
This PET scan was obtained 20 hours after RFA. The rim-shaped uptake had
cleared on PET performed 3 months after RFA, leaving total photopenia.
However, focal uptake at the edge of this photopenic area was seen 7 months
after RFA, and subsequent PET scans showed increased size and intensity, which
is compatible with residual tumor at the time of ablation. We hypothesize that
either this residual tumor was macroscopic and hidden by inflammatory
(rim-shaped) uptake on the early PET scan or there was only microscopic
residual disease at the time of ablation. In any case, findings on two MRI
scans obtained 3 and 5 months after RFA were compatible with postablation
changes at the RFA site and did not lead to the diagnosis of residual tumor
either. Finally, MRI performed at 8 months after RFA led to the diagnosis of
the residual tumor.
Discussion
In our pilot series of RFA-treated patients, seven of eight (88%) patients
had no inflammatory uptake on early PET; findings on early PET were predictive
of outcome in six of seven (86%) patients. There were four true-negatives with
total photopenia and complete ablation, one false-negative with total
photopenia but microscopic residual tumor, and two true-positives with focal
uptake, indicating nonablated macroscopic tumor. Apparent inflammatory uptake
was seen in only one lesion (13%) and was less frequent than in the series by
Veit et al. [9] (five of 15
metastases). The one patient with probable inflammatory uptake in our series
underwent PET 20 hours after RFA, in contrast to the series by Veit et al. in
which the patients with apparent inflammatory uptake underwent PET on the
second post-RFA day. On the other hand, the two patients who underwent PET in
our series on the second post-RFA day (patients 1 and 4) did not have any
inflammatory uptake. Given the small number of subjects in both series, no
statistically meaningful conclusions can be drawn regarding the best time
point to perform early PET. In addition, in our series, patient 8 underwent
follow-up for only 3 months and microscopic residual tumor cannot be ruled
out, although the objectives of visualizing the absence of macroscopic
residual disease and inflammatory uptake were achieved.
Large prospective studies with adequate follow-up time in all subjects are
needed to estimate the sensitivity and specificity of early PET in detecting
residual tumor after RFA of hepatic metastases. While considering various time
points for early PET, one must keep in mind that, because of postoperative
pain, patients with laparoscopic and laparotomic RFA are unlikely to be able
to tolerate PET on the same day as RFA or perhaps even on the day after RFA,
as was the case with the subjects in our study. All patients studied by Veit
et al. [9] underwent
percutaneous RFA, which results in significantly less pain.
In conclusion, there is infrequent inflammatory uptake at the RFA site of
liver metastases on 18F-FDG PET if scanning is performed within 2
days after ablation. Thus, we conclude that early PET has the potential to
evaluate the efficacy of an RFA procedure by indicating macroscopic tumor-free
margin as total photopenia and macroscopic residual tumor as focal uptake.
Such an assessment would allow a second RFA treatment to be performed
early—at a time when efficacy is likely to be higher than if waiting for
a lesion to appear on CT or MRI months later. This new area of potential PET
use warrants further investigation. Our study is a first step in that
direction.
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Abstract
Introduction
