Background
Renal cell carcinoma (RCC) accounts for 3% of all adult cancers [
1]. Approximately 30% of patients are diagnosed with metastases and an additional 20-40% of patients develop metastases after radical nephrectomy with curative intent [
2,
3]. The outcome of patients with metastatic RCC is poor, with a median survival time of 10 to 21 months [
4,
5]
Classical cytokine therapies have been the only systematic treatments available for advanced RCC for a long time [
6‐
9]. The oncogenic mechanism of RCC has been elucidated and agents that target relevant biological pathways have been investigated. Multiple tyrosine kinase inhibitors (multiple TKIs) targeting vascular endothelial growth factor receptor (VEGFR) such as sunitinib and sorafenib have revolutionized the treatment of RCC [
10,
11]. Although mammalian target of rapamycin (mTOR) inhibitor was not available in Japan at the time of this study, the efficacies of mTOR inhibitors have been reported [
12,
13]. These developments have made it necessary to predict the prognosis of individual patients with advanced RCC and to select optimal management. Many clinical risk factors have been proposed, and classifications of patients using these risk factors have been established. The most common classification was proposed by the Memorial Sloan-Kettering Cancer Center group for cytokine-based therapies (MSKCC classification)[
14], and modified criteria adapted for the new era of molecular targeting was reported recently and recommended in the National Comprehensive Cancer Network guideline (NCCN classification)[
12,
15]. However, these classifications are not enough to determine the best treatment selection for an individual patient. Novel biomarkers to predict the prognosis of individual patients are therefore desired.
During the last decade, 18-fluoro-2-deoxy-D-glucose positron emission tomography (
18F-FDG-PET) emerged as a useful non-invasive tool to evaluate the metabolic status of tumors. Numerous recent studies of various types of malignancies have reported an association between the
18F-FDG accumulation rate evaluated by PET and patient prognosis. The standardized uptake value (SUV) is a semiquantitative simplified measurement of the tissue FDG accumulation rate, and studies of the head-and-neck, lung, and cervical cancer have explored the prognostic significance of the maximum standardized uptake value (SUVmax) [
16‐
19]. However, the role of the SUVmax as a prognostic factor for patients with advanced RCC has not yet been evaluated. In the present study, we evaluated prospectively the impact of SUVmax on the survival of patients with advanced RCC.
Methods
Patients
This was a prospective study to clinically follow enrolled patients planning to undergo systematic therapies for advanced RCC. In principle, the pathologies of enrolled cases were confirmed by prior nephrectomy or biopsy, but only one case was diagnosed clinically by conventional imaging because the patient wished to be treated immediately and did not consent to biopsy. The patients were initially assessed by conventional imaging techniques (computed tomography [CT], magnet resonance imaging [MRI], or bone scintigraphy) and diagnosed as stage IV or metastatic RCC. Patients with uncontrolled diabetes mellitus, with other known malignancies and treated with therapeutics the last 2 weeks before the scan were excluded.
The study protocol was approved by the Yokohama City University Institutional Review Board. Written informed consent was obtained from all patients. The patients underwent various therapeutic interventions decided before the evaluation by PET/CT at Yokohama City University Hospital and Kanagawa Cancer Center.
Imaging
Patients fasted for at least 6 hours prior to intravenous injection of [18F] FDG. PET/CT images were obtained using a PET/CT system (Aquiduo 16; Toshiba Medical Systems, Tokyo, Japan). PET/CT images were acquired from the top of the head to the mid thigh at 60 min after intravenous injection of 2.5 MBq/kg of [18F] FDG. A low-dose non-contrasted CT scan was acquired first and used for attenuation correction. Emission images were acquired in 3-dimensional mode for 2 min per bed position. After PET acquisition, CECT was performed with a 2-mm slice thickness, 120 kV, 400 mA, 0.5 s/tube rotation, from the top of the head to the mid thigh, with breath holding. A total of 100 ml contrast medium (iopamidol) was administered intravenously at a rate of 1.0 ml/s. The scan delay was set at 120 s after starting the injection of contrast material. Images were reconstructed by attenuation-weighted ordered-subset expectation maximization (OSEM) (four iterations, fourteen subsets, 128' 128 matrix, with 5-mm Gaussian smoothing). The highest SUV in all RCC tumors of each patient was defined as SUVmax. To obtain the SUVmax, the SUV values of all lesions in tumors diagnosed as RCC by CT imaging were analyzed.
Statistical analysis
Survival time was calculated from the date of evaluation by 18F-FDG PET/CT to the date of death. Cox proportional hazards model was used to assess the effects of SUVmax on survival. The cancer-specific survival curve was estimated by the Kaplan-Meier methods, and the resulting curves were compared using the log-rank test. All statistical analyses were carried out with SPSS software (SPSS, Inc, Chicago, IL).
Discussion
In the present study, we demonstrated that the SUVmax evaluated by
18F-FDG-PET/CT is a useful predictive "imaging biomarker" for survival of patients with advanced RCC. PET has not been generally used for the screening of RCC due to the urinary excretion of the radiotracer, which can mask the presence of primary lesions [
20,
21]. However the large RCCs often presenting in stage IV could be evaluated without the influence of urinary excretion of the radiotracer by PET/CT providing combined morphological and functional information (Figure
1). In this study, 7 primary RCC lesions, with diameters ranging from 8.5 cm to 14.7 cm, were examined by
18F-FDG-PET/CT, and abnormal FDG accumulations sufficient to evaluate SUV were detected in all lesions. Pathological diagnosis was confirmed in 6 cases. Distant metastases of RCC could also be detected without interference of excretory radiotracers. We did not confirm the pathologies of the individual metastatic lesions, but the previous report by Majhail
et al. warranted the accuracy of metastasis diagnosis by
18F-FDG-PET. They performed biopsy or surgical resection of 36 distant metastatic lesions in 24 patients that were diagnosed by
18F-FDG-PET, and pathological findings revealed metastatic RCC in 33 lesions (89%) [
22]. In this study, FDG accumulation was evaluated in 94.9% of all RCC lesions diagnosed by CT scan except for lung or liver metastases less than 1 cm. These results were consistent with a previous report [
23] and indicated that the information gained by
18F-FDG-PET/CT was sufficient to characterize advanced RCCs.
In this era of molecular targeting therapy when various systematic treatments can be selected, prognostic biomarkers are required for the purpose of risk-directed therapy selection. We revealed that the SUVmax has the potency as a novel biomarker to predict the survival time of patients with advanced RCC, by multivariate analyses with standard risk factors or risk classifications. FDG accumulation is thought to be indicative of the metabolic activity of a targeted lesion and it has been found to be a useful index in a variety of cancers. It is reasonable that a tumor with high metabolism would show rapid progression and a poor prognosis. It has been reported recently that
18F-FDG PET/CT is useful for evaluating the response to sorafenib and sunitinib treatment of RCC [
24,
25]. The results showing that these therapeutics decrease the FDG accumulation of RCC lesions encourage the hypothesis that the FDG accumulation is indicative of the biological activity of RCC. Additionally, it has been reported that intratumoral neutrophils were detected in RCCs showing poor prognosis [
26]. SUV may reflect not only the biological activity of cancer cells but also the presence of migrating neutrophils.
To our knowledge, this is the first report to evaluate the impact of SUVmax on survival of patients with advanced RCC. However, the number of patients and the follow-up period were limited. Enrollment for this study continues now, and the impact of SUVmax on the survival of patients with advanced RCC will be more apparent from results from an expanded number of patients and follow-up period.
Authors' contributions
Noboru Nakaigawa had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.
Study concept and design: KN, MY, TI, YK, NN
Acquisition of data: KN, RM, KM, NH, TM, FS, UT, KK, SN, HI, TK, TM
Analysis and interpretation of data: KN, MY, NN
Administrative, technical, or material support: TI, YK, NN
Drafting of the manuscript: KN
Critical revision of the manuscript for important intellectual content: MY
Obtaining funding and supervision: NN