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1
Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of
Medicine, Kyoto University Hospital, 54 Shogoin-kawahara-cho, Sakyo-Ku, Kyoto,
606-8507 Japan.
2
Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto
University Hospital, Kyoto, 606-8507 Japan.
3
Department of Radiology, Hamamatsu University School of Medicine, 3600 Handa,
Hamamatsu, 431-3192 Japan.
Received August 8, 2000;
accepted after revision December 7, 2000.
Address correspondence to T. Saga.
Abstract
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SUBJECTS AND METHODS. Twenty-four women who had undergone surgery or chemoradiotherapy for histopathologically proven ovarian cancer were enrolled in this study. Ovarian cancer was thought to have recurred in 12 of these women because of evidence on conventional imaging modalities or tumor marker measurements (group A). Clinical findings for the remaining 12 women showed them to be disease-free (group B). PET findings for the women were compared with the final diagnoses obtained by histopathology or by clinical follow-up. The clinical contribution of PET was assessed by evaluating whether PET yielded information complementing the findings of conventional modalities and by examining its impact on treatment.
RESULTS. PET gave valuable information for seven of 12 patients in group A in addition to the information obtained from findings on conventional imaging, and treatment was affected in five patients. On the other hand, in group B, additional information was obtained in only three of 12 patients, and treatment of only one patient was affected. Overall sensitivity, specificity, and accuracy of conventional imaging modalities were 72.7%, 75.0%, and 73.3%, respectively, and these rates improved to 92.3%, 100.0%, and 94.4%, respectively, by considering both conventional imaging modalities and PET findings.
CONCLUSION. Our preliminary data suggest that whole-body PET with FDG can be a complementary modality for following up patients who have had ovarian cancer, especially patients believed to be at risk for recurrence.
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Recent progress in diagnostic imaging, especially MR imaging and helical CT with contrast enhancement, has made possible the characterization of ovarian cancer [5,6,7,8]. However, correctly diagnosing recurrence using only these conventional imaging modalities can be difficult because small disseminated lesions sometimes cannot be identified, and even measurable tumors cannot always be definitely diagnosed as recurrence. In oncologic nuclear medicine, some attempts have been made to detect recurrent foci using tumor-specific monoclonal antibodies. In the case of ovarian cancer, the immunoscintigraphic technique was reported to be a sensitive method for the detection of local recurrence [9,10,11], but it seems to be of limited use, and its spatial resolution is relatively low. Thus, second-look laparotomy has been performed in patients with symptoms suggestive of recurrence. However, determining disease status accurately is not easy when no gross tumor is seen, and even second-look laparotomy is not perfect for detecting all the small lesions in the abdominal cavity because of the possibility of adhesions. In addition, the procedure is of no help in the detection of distant metastases.
Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has been shown to be a useful tool for imaging recurrent cancers, such as colorectal cancers [12,13,14]. PET can sometimes detect the location of recurrent foci even when they are invisible on other conventional imaging modalities, and PET can allow physicians to distinguish recurrent diseases from postoperative scars. Until now, however, the clinical application of PET using FDG for gynecologic malignant tumors has been relatively limited, and, so far, there have been few reports describing the usefulness of the technique, especially in patients with recurrent ovarian cancer [11, 15,16,17].
In our prospective study, we assessed the clinical value of whole-body PET as a complementary modality in the follow-up of patients previously treated for ovarian cancer.
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PET
Fluorine-18 was produced by a 20neon (d, 
)
18fluorine nuclear reaction in a cyclotron, and FDG was synthesized
by the acetyl hydrofluorite method
[18]. The patients fasted for
at least 5 hr before the injection of the FDG. For six women in this study, we
used a PET camera (PCT3600W; Hitachi Medico, Tokyo, Japan) with eight rings,
which provided 15 tomographic sections at 7-mm intervals and with an intrinsic
resolution of 7 mm full width at half-maximum intensity. With this machine, a
10-min transmission scan of the pelvis was obtained before injection of
approximately 370 MBq of FDG, and a 10-min emission scan of the same region
was obtained 60 min after the injection. Thus, pelvic axial images with
attenuation correction were obtained. For the remaining 18 women, PET was
performed using a high-resolution, whole-body PET scanner with an 18-ring
detector arrangement (Advance; General Electric Medical Systems, Milwaukee,
WI). The system permitted the simultaneous acquisition of 35 axial images with
interslice spacing of 4.25 mm. Axial resolution was 4.2 mm full width at
half-maximum intensity, allowing multidirectional reconstruction of the images
without loss of resolution. The field of view and pixel size of the
reconstructed images were 256 mm and 2 mm, respectively. Approximately 370 MBq
of FDG was IV injected, and whole-body PET images without attenuation
correction were acquired approximately 60 min later.
To avoid artifacts caused by urinary tract activity, we gave six patients IV hydration (1000 mL of saline) and 20 mg of furosemide, and placed a triple-lumen Foley catheter in the bladder for continuous irrigation and drainage before imaging the pelvis. In the other patients, the PET scan was obtained just after patients had voided.
Conventional Imaging
CT scans were obtained in patients (scanners: W3000, Hitachi Medico: or CT
HiSpeed Advantage, General Electric Yokogawa Medical Systems, Tokyo, Japan)
before and after administration of nonionic contrast material. Patients were
given 100-150 mL of contrast material via machine injection at a rate of 2
mL/sec, and scanning in the abdomen or pelvis began 2 min after the start of
contrast injection. The images were interpreted by the consensus of at least
three experienced radiologists who were unaware of the PET findings.
MR imaging was performed using a 1.5-T superconductive system (Signa; General Electric Medical Systems) with a body coil, with which we obtained sagittal and axial T2-weighted fast spin-echo images. Contrast-enhanced T1-weighted fast spin-echo images using 0.1 mmol/kg of gadopentetate dimeglumine (Magnevist; Schering, Osaka, Japan) were obtained by the conventional spin-echo technique with the fat-saturation method when needed. The parameters for T1-weighted imaging were 600/20 msec (TR/TE), and those for T2-weighted imaging were 5000/80-90 (TR/TE range). For each image, slice thickness was 5 mm with a 2.5-mm gap, a matrix of 256 x 192, 2 signals averaged, and a 32-cm field of view. The MR images were interpreted by the consensus of at least four experienced radiologists. In all patients in group A, conventional imaging examinations were performed within the 3 weeks (mean, 7.9 days) before PET was performed. In group B, six of the 12 women underwent conventional imaging examinations before PET (mean, 10.5 days), and the remaining six women had follow-up conventional imaging studies performed after PET.
Image Analysis of PET
All PET images were interpreted using all available clinical information
and correlative conventional imaging. PET images were interpreted by the
consensus of at least three experienced nuclear medicine physicians.
Semiquantitative analysis was not done in this study because
attenuation-corrected images were not obtained using the whole-body camera.
For our purposes in this study, the original clinical PET interpretation
criteria were used. Image interpretation criteria were those routinely used in
scintigraphic imaging. Lesions were identified as being an abnormal finding or
representative of tumor if the accumulation of FDG was moderately to markedly
increased relative to comparable normal contralateral structures or
surrounding soft tissues. Evidence of mildly increased activity or—in
the case of an abnormality identified on conventional imaging with no
corresponding PET abnormality—no increased activity was considered to be
a normal finding or indicative of benign disease.
The FDG PET findings were related to the final diagnoses obtained by histopathology (n = 10), cytology (n = 1), or at least 6 months of clinical follow-up (n = 12) (range, 193-532 days; mean, 373 days) including imaging studies. In addition, we included one patient whose follow-up period was less than 6 months but whose follow-up CT scan revealed a lesion corresponding to PET findings of increased uptake in the area in which the lesion was found; the lesion responded to chemotherapy. The term "additional information" was defined as findings obtained only by PET; for example, PET detected some lesions that had not been detected by conventional imaging modalities, or PET revealed characteristics of a lesion that had been interpreted as an inconclusive finding on conventional imaging. The term "clinical impact" was used when patients' treatment changed as a result of the PET findings.
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In group B, PET showed true-positive results in two of 12 patients and true-negative results in eight of 12 patients. In one of the remaining two patients, three disseminated lesions smaller than 1 cm were identified in the peritoneum by second-look laparotomy (false-negative finding). In the other remaining patient, a viable tumor was suspected in the left adnexal region, but no tumor was found at surgery (false-positive finding). The additional information was obtained in three (25.0%) of 12 patients—two patients had the staging of their cancer moved up a stage and one had viability confirmed. Clinical impact was found for one (8.3%) of 12 patients; treatment was changed from follow-up to surgery.
Diagnostic accuracy is shown in Tables 1 and 2. On the patient-based analysis, overall sensitivity, specificity, and accuracy of conventional imaging modalities for 15 patients were 72.7%, 75.0%, and 73.3%, respectively, with three inconclusive cases excluded. When results of both PET and conventional imaging were considered, sensitivity, specificity, and accuracy improved to 92.3%, 100.0%, and 94.4%, respectively (n = 18). Concordance and discordance between PET and conventional imaging modalities are summarized in Table 3. Figures 1A,1B,1C and 2 are images from representative patients for whom FDG PET provided additional information.
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On the other hand, CT and MR imaging techniques in the field of gynecologic oncology recently have been improved. For example, it has been reported that detectability of peritoneal disease was improved with the use of contrast-enhanced fast multiplanar spoiled gradient-recalled MR imaging [5]. However, in clinical settings, accurate diagnosis of peritoneal dissemination is often difficult using only morphologic modalities. FDG PET is, therefore, expected to provide functional imaging that is not possible with conventional imaging modalities. Moreover, the newer PET machines can image the whole body and detect unexpected lesions outside the pelvis. There are some articles on examining patients with ovarian cancer by PET [11, 15,16,17, 19], but the clinical value of whole-body FDG PET for recurrent ovarian cancer remains uncertain. We investigated the clinical contribution of PET, focusing on additional information and clinical impact, because PET will be most valuable as an adjunct to conventional imaging in following up patients.
In detecting recurrence of ovarian cancer, PET had a fairly good rate of diagnostic accuracy (79.2%). When combined with results of conventional imaging modalities, its accuracy was improved to 94.4%. Just as PET has been useful in detecting recurrent colorectal cancer, it can be a complementary modality in detecting recurrent ovarian cancer when findings by conventional imaging are inconclusive. Eight of the nine lesions initially interpreted on conventional imaging modalities as having inconclusive or negative findings were accurately diagnosed as having positive findings on PET in our series.
According to lesion-based analysis, discordance occurred in approximately half of the lesions. Five of six lesions interpreted as showing inconclusive findings on conventional imaging were accurately diagnosed using PET. In patients whose results were positive on PET and negative on conventional imaging, CT or MR images were reinterpreted by radiologists with the knowledge of PET findings and, even in retrospect, none of the lesions could be detected.
Overall, additional information was obtained by PET for more than one third of our patients. However, the effect of PET results on clinical impact was not as great as expected. Therefore, PET contributes to the physicians' estimation of a patient's actual status, but it has a limited value for helping them to decide on treatment for recurrent ovarian cancer. This finding may be attributable to the recognized effectiveness and importance of chemotherapy using paclitaxel plus cisplatin or carboplatin, especially in the treatment of ovarian cancer [20, 21].
One of the problems of a PET study is nonpathologic uptake in the alimentary and urinary tracts. Physiologic uptake observed in the stomach, colon, ureter, and bladder are sometimes difficult to differentiate from that observed in pathologic lesions. Such accumulation may mask abnormal uptake to tiny disseminated lesions. In addition, accumulation of FDG by inflammatory processes has made PET a controversial modality [22, 23]. The combination of hydration, administration of a diuretic such as furosemide, and use of a Foley catheter with a drainage bag is an effective method of reducing physiologic uptake in the kidneys, ureter, and bladder [24], but reducing the physiologic uptake in the colon is difficult. Further investigations are needed to eliminate this physiologic uptake in noncancerous tissues.
Another problem is false-negative results for small lesions, such as the lesions in peritoneal dissemination; in other words, PET can miss poorly localized microscopic spread of disease. As previously reported in studies of colorectal cancer and as we found in this study, lesions smaller than 1 cm were quite difficult to identify not only because of the relatively poor spatial resolution of this modality but also because of the longer acquisition time of PET compared with that of conventional imaging modalities (4 min per bed position in our study). Count recovery from small lesions may not be sufficient because of peristalsis of the alimentary tract and respiratory movement during image acquisition. Thus, even if PET findings are negative, small lesions sometimes may be detected by second-look laparotomy. However, follow-up patients typically receive chemotherapy for recurrence and systemic metastasis. Very small lesions that cannot be detected on PET scans may be sensitive to drugs, although larger lesions are resistant, perhaps because of penetration barriers [25, 26]. Therefore, if FDG PET reveals highly accumulated lesions remaining in a patient even after repeated chemotherapy, resection would be recommended. If PET findings are negative, chemotherapy may be proposed because some small lesions may remain. Thus, PET can be useful for determining therapeutic treatment.
Recent improvements in PET have made it possible to examine the patient's whole. This feature is an advantage that other imaging modalities lack, and indeed some unexpected metastases were identified. Tumor markers and conventional imaging have been used for clinical workup, but as PET comes into wider use, a patient may be screened for recurrence of disease by PET before undergoing conventional imaging. The high cost of PET examination remains a barrier to its use as a screening procedure, but if PET can obviate other unnecessary examinations and help to detect recurrence earlier, thereby improving a patient's prognosis, then it has potential as a screening tool for postoperative patients. However, the most effective use of PET currently is as a complementary tool for those patients who have inconclusive or indeterminate findings on conventional imaging. Further study is needed to determine the optimal use of PET in the follow-up care of postoperative women with ovarian cancers.
In our study, attenuation correction was not performed for whole-body scanning, and we used qualitative analysis for diagnosis. Attenuation correction is time-consuming, the images are sometimes degraded, and it has been reported that radiologists' ability to detect lesions in attenuation-corrected images is lower than in non—attenuation-corrected images [27]. Thus, we evaluated non—attenuation-corrected images in most patients in this study. However, we have recently discovered that small pancreatic cancers were clearly detected only by attenuation-corrected images reconstructed with an ordered-subsets expectation maximization algorithm. Further investigation of the optimal acquisition and reconstruction may be necessary to obtain higher detection rates.
There are many types of ovarian cancer. PET images the hypermetabolic state of glucose in malignant tissues irrespective of the histology, and there could be some types of tumors that do not take up FDG well. In our series, measurable tumors were detected on PET scans, except for a residual mass discovered after the patient received chemotherapy. However, the limitations of FDG PET in detecting mucinous neoplasm have been mentioned in the literature [28]. Therefore, PET is likely to have some limitations as a tool in detecting recurrent disease of mucinous cystic tumor, although it is hard to draw any conclusions from this study. We had only two patients with true-negative findings for mucinous cystadenocarcinoma. Further studies are needed to evaluate whether PET is of value in detecting all types of ovarian cancer.
One of the limitations of this study was obtaining correct diagnoses by follow-up. Small distant lesions may be missed even at surgery, although findings at surgery were used as the gold standard. Positive findings are easy to confirm, but negative findings only mean that we could not acquire positive findings during the follow-up period, so we remain uncertain whether the findings are truly negative. Furthermore, there was one patient who received chemotherapy without confirmation of recurrence during the follow-up period. We treated the findings for this patient as true-negative results on the basis of the follow-up results. In using FDG PET to detect recurrence, we may not be able to say that the findings we obtain are definitely negative.
From this preliminary study, we concluded that whole-body PET using FDG is a useful complementary modality for detecting recurrent sites in follow-up patients with ovarian cancer, and a clinical contribution could be expected, especially in patients with clinical findings suggestive of recurrence. However, we found that PET had limitations as a tool in detecting small lesions. It may be difficult to replace the second-look laparotomy as a method of detecting tiny lesions, but PET, as a noninvasive imaging tool, should be considered when examining a patient in whom recurrent ovarian cancer is suspected.
Acknowledgments
We thank Toru Fujita, Takahiro Mukai, and Haruhiro Kitano for their
excellent technical assistance and Milliam L. Kataoka for her comments on MR
imaging. Also, we thank Bryan J. Traughber for his editorial assistance.
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