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Clinical Observations |
1 Department of Surgery, University Hospital Groningen, Hanzeplein 1, PO Box
30001, 9700 RB Groningen, The Netherlands.
2 PET-Center, University Hospital Groningen, Groningen, The Netherlands.
3 Office for Medical Technology Assessment, University Hospital Groningen,
Groningen, The Netherlands.
Received August 13, 2004; accepted after revision September 27, 2004.
Address correspondence to H. L. van Westreenen.
OBJECTIVE. On PET, the level of tissue glycolysis can be quantified by the accumulation of fluorine-18-fluorodeoxyglucose expressed as the standardized uptake value (SUV). The aims of this study were to investigate the relation between SUV and the stage of disease and whether SUV can be used to predict resectability and survival in patients with esophageal cancer.
CONCLUSION. SUV can be used to predict resectability; however, SUV is not an independent factor that can be used to assess survival in patients with esophageal cancer.
PET is a noninvasive imaging technique that is frequently applied in the diagnosis and staging of different types of cancer [1]. The increased glucose metabolism of malignant cells is the driving force for the uptake of fluorine-18-fluorodeoxyglucose (18F-FDG), which is currently the most common radiotracer used for oncologic PET studies [2, 3]. 18F-FDG is phosphorylated solely intracellularly by the enzyme hexokinase, which causes intracellular entrapment as FDG-6 phosphate and enables adequate measurement of the tissue glycolysis level.
In addition to staging, PET is able to quantify 18F-FDG uptake in malignant tissue. The usually applied quantification parameter in clinical FDG-PET is the standardized uptake value (SUV). SUV is determined by the ratio of activity in tissue (Bq/mL) and the decay-corrected activity of 18F-FDG injected into the patient (Bq/g) [4]. In general, the degree of tumor proliferation correlates with its metabolic activity. Because tumor proliferation is related to clinical behavior, which determines prognosis, SUV calculations may enable FDG-PET to be used to predict the prognosis of patients with and the proliferation of several malignancies [5–7].
In esophageal cancer, FDG-PET has been accepted as a useful tool for the detection of distant metastatic disease, and SUV might also be useful to predict patient survival and the aggressiveness of esophageal cancer before surgery [8–10]. However, data about the clinical application of SUV measurements in these patients are scarce [11, 12].
For this study, we quantitatively evaluated the metabolic activity of cancer of the esophagus and gastroesophageal junction using FDG-PET and SUV analyses. Furthermore, the predictive value of SUV independent of established prognostic factors was determined with univariate and multivariate analyses.
Materials and Methods
Patients
This study comprises a retrospective analysis of 40 consecutive patients
with cancer of the esophagus or gastroesophageal junction diagnosed between
January 2001 and December 2002. FDG-PET was performed in patients who were fit
to undergo surgery and in those without evidence of metastases from routine
history, physical examination, and laboratory test results. Ten patients who
underwent FDG-PET on an ECAT 951/31 scanner (CTI, Siemens) were excluded from
our analysis because there was no opportunity for attenuation correction of
that data.
The study group was composed of 24 men and 16 women with a median age of 64.6 years (range, 48–79 years). None of these patients was treated with preoperative chemotherapy. Patient characteristics are summarized in Table 1. All cases were staged further with endoscopic sonography and CT according to the classification established by the Union Internationale Contre le Cancer (UICC) [13]. Nineteen patients underwent a radical transthoracic esophagectomy. The remaining patients were treated with a palliative regimen including radiation therapy, endoluminal stenting, or both.
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CT
CT was performed using a single-detector helical scanner (Tomoscan SR 7000,
Philips Medical Systems). CT scans were obtained from the neck to the upper
abdomen including the liver. CT of both the thorax and the abdomen was
performed with a 10-mm collimation. The reconstruction interval was 5 and 10
mm for the thorax and abdomen, respectively. Beginning in January 2002,
examinations were performed on an MDCT scanner (Somatom Sensation, Siemens
Medical Solutions). MDCT scans were obtained with a 3-mm collimation and a
reconstruction interval of 1.5 mm. Scans were obtained with both IV and oral
contrast material.
Endoscopic Sonography
A radial scanner (GF-UM20 [7.5–12 MHz], Olympus) was used for the
performance of endoscopic sonography. Endoscopic sonographically guided
fine-needle aspiration of suspected celiac lymph node metastases was
performed. The biopsy sample was obtained via a separate linear-array
echoendoscope (FGUX-36 [5–7.5 MHz], Pentax Benelux). If a stenotic tumor
could not be passed with the GF-UM20 scope, a small-caliber probe (MH-908 [7.5
MHz], Olympus) was used in an attempt to traverse the tumor.
PET
PET was performed using an ECAT HR+ positron emission camera (CTI,
Siemens). This camera acquires 63 planes over a 15.8-cm axial field of view.
Patients fasted for at least 4 hr before 130–690 MBq (median, 230 MBq)
of 18F-FDG was administered IV (3 MBq/kg). Data acquisition started
90 min after injection in the whole-body mode (2D), and data were acquired for
5 min per bed position from the knees to the skull. Transmission imaging was
performed for 3 min per bed position for attenuation correction using the
emission–emission transmission–transmission (EETT) method. Data
from multiple bed positions were iteratively reconstructed (ordered subset
expectation maximization) yielding both attenuated and nonattenuated
whole-body PET images
[14].
Evaluation of 18F-FDG Uptake
A 3D region of interest (ROI) was selected semiautomatically using a
dedicated software program. The ROI was placed over the tumor on multiple
slices using a threshold of 70% of the maximum pixel value within the tumor.
The maximum SUV (SUVmax) denotes the maximum SUV value within the
tumor ROI, and the mean SUV (SUVmean) is the mean value averaged
over all voxels. These values were calculated according to the following
equation:
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Data Analysis
The relationships between 18F-FDG uptake of primary esophageal
carcinomas and the characteristics of the patients, including sex and age, and
the characteristics of the tumor, including the UICC stage, histology, and
resectability, were assessed by the Student's t test or analysis of
variance as appropriate. For survival analysis, the study group was divided
into two subgroups: one with low SUVs and one with high SUVs using the median
SUVmax value or the median SUVmean value as the cutoff
value. Survival data were analyzed using the Kaplan-Meier method, and
differences in the cumulative survival rate between subgroups were compared
with the log-rank test. Furthermore, SUVs and survival data were entered in a
linear regression analysis.
To discover independent prognostic factors, we performed stepwise multivariate analysis of survival using Cox's proportional hazards model. The following factors were entered as independent variables: patient sex; patient age; and tumor histology, localization, UICC stage, SUVmax, and SUVmean; and type of treatment. All p values were two-tailed, and significance was considered as a p value of less than 0.05.
Results
Ten of the 40 patients had stage I or II disease (T1–2 N0–1 M0), 13 had locally advanced stage III disease (T3–4 N1 M0), and the remaining 17 had stage IV disease (TX NX M1). Nineteen patients had a curative resection including a two-field lymphadenectomy. Twenty-one patients underwent palliative treatment including intraluminal stent placement, radiation therapy, or both.
The median SUVmax for all 40 patients was 6.7, ranging from 1.8 to 19.2. The SUVmean ranged from 1.4 to 15.7 (median, 5.7). The median follow-up time after PET was 321 days (range, 7–934 days). One patient died postoperatively on day 7. Patient characteristics and comparisons of SUVmax and SUVmean in each of the subgroups are summarized in Table 1.
No significant differences in the SUVmax and SUVmean with respect to patient sex, patient age, or tumor localization were detected. However, SUVmax and SUVmean differed significantly for UICC stage; T, N, and M classification separately; and type of treatment.
Univariate survival analysis for various patient characteristics is shown in Table 2. The cumulative survival rate was significantly decreased in patients with distant metastases (p = 0.022) and in patients who were not eligible for resection (p = 0.0001). Patients with high SUVmax (SUV > 6.7) and high SUVmean (SUV > 5.7) had a worse survival rate than patients with low SUVs (p = 0.016). Figure 1A, 1B shows the comparison between SUVmax and SUVmean of the primary tumor versus patient survival. Linear regression analysis showed a low correlation between SUV and survival (r = 0.36). Figure 2 shows the Kaplan-Meier cumulative survival plot for patients with high SUVs and those with low SUVs; the survival plots for SUVmax and SUVmean were identical.
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Because of possible interrelationships among prognostic factors, multivariate analysis was performed. Multivariate Cox regression analysis showed that resection was the only independent predictor of survival (p = 0.0003; 95% confidence interval, 0.065–0.445). SUV did not have an additional impact on estimating patient survival independent of resectability.
Discussion
The results from this study show that patients with high SUVs have a poorer survival rate than patients with low SUVs. This was found for both the SUVmax (cutoff value, 6.7) and SUVmean (cutoff value, 5.7) of the tumor. However, multivariate analysis showed that resection was the only independent factor for the prediction of patient survival. This is expressed by a significantly lower SUV in the patients who were eligible for resection. Therefore, SUV did not have a significant additional impact on estimating patient survival.
Literature about the relationship between SUV and survival in patients with esophageal cancer is scarce. Several authors reported that survival was significantly lower in patients who had high SUVs and reported a great variety in the cutoff values, ranging from 3 to 7 [11]. These results are in agreement with those from this study. However, the other studies did not examine the role of SUV in the prediction of patient survival using multivariate analysis.
Most patients in this study had an adenocarcinoma, whereas the patients of most other studies had squamous cell carcinoma. Overexpression of glucose transporter 1 (GLUT-1) has been shown especially in squamous cell carcinoma and was correlated with a higher SUV and a worse prognosis [15–17]. No differences in GLUT-1 expression between adenocarcinoma and squamous cell carcinoma of the esophagus and gastroesophageal junction were reported. Both types showed a significant number of cases expressing this transporter [18]. Menzel et al. [19] found no differences in 18F-FDG uptake between squamous cell carcinoma and adenocarcinoma, underlining that both histologic types are comparable regarding their 18F-FDG uptake.
The retrospective design of our study hampers us from drawing solid conclusions from our results. Also, the actual cutoff values used in this study cannot be extrapolated to other series because technical issues such as ROI definitions, scan processing, and acquisition protocols vary among centers. A large prospective trial may reveal the use of SUVs in the prediction of survival in patients with esophageal cancer, especially in a large series of patients with identical treatment and scanning protocols.
In conclusion, SUV analysis should be performed because a high SUV seems to be related to advanced stages of esophageal carcinoma; unresectability; and, therefore, poor prognosis. However, SUV is not useful as an independent predictor of survival in patients with esophageal cancer. Because esophagectomy is the only potentially curative option, patient survival is strongly predicted by the eligibility for surgery.
References
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