KIDSTAGE- Staging of Kidney Cancer Using Dual Time PET/CT and Other Biomarkers

Background Renal cell carcinoma (RCC) represents 2-3% of all malignancies, and the European prevalence is approximately 84,400 cases per year [1]. In Denmark 950 new cases of Kidney Cancer (KC) are diagnosed per year, and the incidence is increasing annually. KC is more common in men than in women and the cancer debuts most frequently in the age of 60-70 years [2]. Early stages of KC are often asymptomatic and the disease is thus often at advanced stage or even metastatic when discovered. Metastases including lymph node metastases are a predictor of bad prognosis. Surgical removal of cancerous lymph nodes has been shown to improve response to systemic treatment and prolong survival [3], but the current methods for detection of especially lymph node metastases are insufficient. Improved methods for detection of metastatic lesions at the time of diagnosis would be of great help for the clinicians who have to select the optimal treatment strategy for the patients. Surgery is the only curative treatment and also the predominant choice of treatment when possible. Systemic treatment is only used in case of metastatic disease. Metastatic KC is generally non-responsive to chemotherapeutics and radiation therapy [2], but a range of other systemic treatment options has been developed over the last decade. This means that it is of increasing importance to monitor how patients are responding to the selected treatment and switch to a different product if the tumor is not responding. The number of patients with KC identified by chance has increased along with an increasing use of routine imaging for a number of others disorders [4]. It is still likely that new and improved methods for early detection of cancer would improve the survival in KC patients.

PET/CT:

Positron Emission Tomography (PET) combined with computed tomography (CT) is a well-established method of diagnosing and staging several types of cancer. 2-deoxy-2-[18F]fluoro-D-glucose (FDG) is the most common PET tracer used in oncologic studies. PET/CT is not a standard modality in the diagnosis and staging of RCC [5]. The sensitivity as to detection of the primary tumor is hampered by the physiological excretion of FDG in the urine. Furthermore, histological characteristics of the tumor such as grade and expression of glucose transporters can affect the FDG uptake negatively [6]. However, PET/CT performs well in detection of extra-renal metastases [7, 8] and proved to be of prognostic value in recurrent RCC [9].

FDG is accumulated in cells with increased glycolysis, in particular cancer cells. FDG accumulation is not specific to tumors and is also seen in benign processes such as inflammation and infection. This makes it difficult to distinguish malignant neoplastic lesions from the benign ones [10]. In recent years the concept of dual-time point (DTP) imaging has evolved. The increase in FDG uptake seems to continue for hours after injection in malignant tissue whereas FDG uptake in normal or inflamed tissue reaches maximum uptake earlier and declines thereafter. Thus, late imaging is thought to result in increased FDG uptake, decreased blood and urine activity and, thus, a better target-to-background ratio and, therefore, a higher sensitivity [11]. Several studies using DTP PET/CT have been performed on tumors in the breast, liver, lung, and prostate. Results indicate that the pattern and rate of FDG uptake over time vary considerably between malignant and benign processes and that DTP PET/CT allows for distinction between them [12,13]. Hitherto, the use of DTP imaging in RCC was scantily reported. A recent paper considered the value of DTP imaging of the primary renal tumor but not of the metastases [14].

Circulating tumor DNA There is a general and increasing interest in circulating cancer biomarkers because they might constitute representative readouts of both primary tumor and metastatic deposits. Furthermore, circulating markers may provide a tool for monitoring response to systematic adjuvant therapies even after the primary tumor has been removed. Promising results have been obtained for blood-born cell free DNA (cfDNA) which can be isolated from a simple blood sample, often referred to as a liquid biopsy. In contrast to tissue biopsies, detection of cfDNA from peripheral blood is a minimally invasive way to monitor the disease during treatment and follow-up.