JNCCN NCCN Task Force Report: PET/CT Scanning in Cancer

The use of positron emission tomography (PET) is increasing rapidly in the United States, with the most common use of PET scanning related to oncology. It is especially useful in the staging and management of lymphoma, lung cancer, and colorectal cancer, according to a panel of expert radiologists, surgeons, radiation oncologists, nuclear medicine physicians, medical oncologists, and general internists convened in November 2006 by the National Comprehensive Cancer Network. The Task Force was charged with reviewing existing data and developing clinical recommendations for the use of PET scans in the evaluation and management of breast cancer, colon cancer, non-small cell lung cancer, and lymphoma. This report summarizes the proceedings of this meeting, including discussions of the background of PET, possible future developments, and the role of PET in oncology. (JNCCN 2007;5(Suppl 1):S1–S22) The use of positron emission tomography (PET scanning) is increasing rapidly in the United States. The most common use of PET scanning is related to oncology, especially in staging and managing lymphoma, lung cancer, and colorectal cancer (Figure 1). In November 2006, the National Comprehensive Cancer Network (NCCN) gathered a panel of expert radiologists, surgeons, radiation oncologists, nuclear medicine physicians, medical oncologists, and general internists to review the existing data and develop clinical recommendations for using PET scans in evaluating and managing breast cancer, colon cancer, nonsmall cell lung cancer (NSCLC), and lymphoma. Because of time constraints, the PET Task force limited its review to these four most common oncologic indications. However, PET scan has a role in most other types of cancers, which are reviewed on an annual basis by the NCCN Guideline Panels for individual malignancies. (For further information, please go on-line to the NCCN Clinical Practice Guidelines in Oncology at www.nccn.org.) This supplement summarizes the proceedings of this meeting. The term PET scan refers to either a PET scan or PET/computed tomography (CT) scan, unless otherwise specified. In addition, the PET radiotracer used is F-fluorodeoxyglucose (F-FDG), unless otherwise specified. What is PET and How Does It Work? Imaging can be broadly subdivided into anatomic and molecular, with molecular imaging defined as the “in vivo characterization and measurement of biologic processes at the cellular and molecular level.” PET is considered the prototypical molecular imaging technique, with PET/CT providing combined anatomic and molecular imaging. PET imaging is based on a unique chemical process involving the collision between an electron and a positron arising from a positron-emitting radioisotope, leading to a process known as annihilation that produces two 511-KeV photons emitted at 180°. These photons can be simultaneously detected with a PET scanner, which consists of multiple stationary detectors that encircle the body. Fluorine-18 (F) incorporated into fluorodeoxyglucose (FDG) is the most common tracer used clinically, with a half-life of approximately 110 minutes. Substitution of fluorine for a hydroxyl group blocks metabolism of the tracer. The level of FDG uptake reflects the rate of trapping of phosphorylated FDG (FDG-6P) and thus the rate of glycolysis (Figure 2). PET scans can be performed with multiple tracers (Table 1) to provide information on blood flow, receptor expression, and metabolism. FDG uptake is increased in most malignant tissue and in various benign pathologies, such as inflammatory conditions, trauma, infection, and granulomatous diseases. For example, sarcoidosis causes false-positive PET scans. Benign neoplasms and hyperplastic and dysplastic tissue may also accumulate FDG. Because of the variability of FDG in normal tissue and benign conditions, physicians interpreting the scans must be familiar with the normal pattern of distribution and the benign causes of FDG accumulation to accurately interpret the data. Patient preparation is critical, with the major goals of minimizing tracer uptake in normal issues (e.g., myocardium and skeletal muscle) while maintaining uptake in target tissues (neoplastic disease). The preparation should include, but not be limited to: 1. Pregnancy testing when appropriate. 2. Fasting instruction and no oral or intravenous fluids containing sugar or dextrose (4–6 hours) to maintain normal glycemia and insulinemia. 3. Hydration to reduce accumulated urinary tracer activity in the collecting system and bladder. 4. A focused history regarding diabetes, recent exercise, dates of diagnosis and treatments, medications, and recent trauma or infections. The oncologic applications of PET scanning are based on increased FDG uptake by tumor tissue. Glucose metabolism is the culmination of many different molecular pathways, and interrupting any of these components can result in glycolysis interruption and a change in the PET scan. Although genetic arrays can be considered multiple biomarkers of the myriad underlying metabolic pathways and may identify targets for intervention, PET scans can be considered a type of downstream imaging from biomarkers, reflecting the final common pathway of glucose metabolism, and they can provide real-time monitoring of treatment response. Cyclotrons that produce F and PET scanners have evolved over the past several decades, and current equipment is smaller and easier to use. Mini cyclotrons now available are highly computerized and can be operated by radiopharmacists or technicians. Minicyclotrons can make short-lived isotopes, such as fluorine, carbon, oxygen, or nitrogen. These radionuclides can be incorporated into metabolically important substrates through automated synthesis devices. In the United States, an estimated 55% of PET scanners are PET/CT scanners, and approximately 100% of scanners purchased in the past year have been PET/CT. The original impetus for combining PET/CT scans was to improve attenuation correction and throughput associated with the CT scan. However, PET/CT scans provide more specific anatomic correlation than PET alone, S-2 Supplement NCCN Task Force Report © Journal of the National Comprehensive Cancer Network | Volume 5 | Supplement 1 | May 2007 Figure 1 Growth of clinical PET. Figure 2 FDG uptake in a cancer cell. Source: Data from Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005;202:654–662; and Bos R, van Diest PJ, de Jong JS, et al. Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 2005;46:31–36. and this technology has been widely adopted. A rapid conversion to PET/CT has clearly occurred, and this technique is emerging as the new standard. Most literature has focused on PET rather than PET/CT scans, and the incremental value of the combined scan is only now being rigorously tested. Nevertheless, most clinicians feel comfortable extrapolating data from PET scans to PET/CT scans. Studies have shown that, in some specific clinical situations, the combined image can further clarify the anatomic location of the PET tracer, improve specificity, and thus reduce false-positive results. The CT portion of a PET/CT scan is used for attenuation correction and anatomic localization. A diagnostic quality CT scan similar to that obtained for diagnostic CT-only scans is not necessary to accomplish these tasks, and the CT component of a PET/CT scan is often a low-dose CT scan to minimize patient radiation exposure. Additionally, contrast is not used because it complicates the use of the CT scan for attenuation correction of the PET scan if appropriate algorithms are not used to correct for the high density of some contrast material. Sometimes patients have already undergone a diagnostic CT scan before being referred for a PET/CT. For example, patients who are potential candidates for liver resection will typically undergo an initial diagnostic CT to evaluate the vascular anatomy of the liver, and then be referred for PET/CT to evaluate for extrahepatic metastases. Another common situation is a patient with a history of malignancy who is being followed up with serial CT scans and is undergoing a PET scan to follow-up the CT scan findings. In these situations, the low-dose CT incorporated into the PET/CT is adequate. This implies that if a diagnostic CT scan is indicated, patients must undergo a separate scan. In most current PET/CT scanners, the CT component is comparable to stand-alone CT devices and capable of providing a high-quality diagnostic CT. Therefore, in some institutions, when patients require a diagnostic CT at the same time as PET/CT, it can be performed immediately after the PET/CT with the same CT scanner using normal CT scan technique and contrast. Standardized Uptake Value Aberrant glucose metabolism FDG uptake in malignant tissues and therefore alterations in glucose metabolism may reflect response to treatment. In this sense, FDG can be construed as a biomarker. Various different techniques for assessing the uptake of the tracer attempt to control for background uptake in the blood pool and surrounding tissues, including very sophisticated kinetic studies providing a quantitative analysis. However, a semiquantitative technique, the standardized uptake value (SUV), is most commonly used because of its relative simplicity. The SUV is calculated using the following formula: Activity per unit volume Injected Activity/Body Weight The use of SUV is an area of active research, with the number of citations rapidly increasing for many different tumor types; currently more than 1000 citations are available for SUV values and tumor response. The SUV is most useful if it reflects the uptake localized to the tumor and not the surrounding tissues. Maximum SUV is a better parameter than the average SUV because of the heterogeneity of the Supplement S-3 PET/CT Scanning in Cancer © Journal of the National Comprehensive Cancer Network | Volume 5 | Supplement 1 | May 2007 Table 1 Clinically Used Positron-Emitting Isotopes and Positron-Containing Tracers Positron Isotopes Half-life Postitron Tracers Use F-18 109.7 min NaF Bone imaging