Diagnostica per immagini – Oncologia

Special contribution 18: Recommendations on the use of ¹⁸F-FDG PET in oncology

James W. Fletcher¹, Benjamin Djulbegovic², Heloisa P. Soares², Barry A. Siegel³, Val J. Lowe⁴, Gary H. Lyman⁵, R. Edward Coleman⁵, Richard Wahl⁶, John Christopher Paschold⁷, Norbert Avril⁸, Lawrence H. Einhorn¹, W. Warren Suh⁹, David Samson¹⁰, Dominique Delbeke¹¹, Mark Gorman¹², and Anthony F. Shields¹³

¹Indiana University School of Medicine, Indianapolis, Indiana; ²H. Lee Moffitt Cancer Center at University of South Florida, Tampa, Florida; ³Washington University School of Medicine, St. Louis, Missouri; ⁴Mayo Clinic, Rochester, Minnesota; ⁵Duke University Medical Center, Durham, North Carolina; ⁶Johns Hopkins Medical Center, Baltimore, Maryland; ⁷US Oncology, Newport News, Virginia; ⁸Queen Mary’s School of Medicine and Dentistry, London, United Kingdom; ⁹Brigham and Women’s Hospital, Boston, Massachusetts; ¹⁰Blue Cross and Blue Shield Association, Washington, DC; ¹¹Vanderbilt University Medical Center, Nashville, Tennessee; ¹²National Coalition for Cancer Survivorship, Washington, DC; and ¹³Karmanos Cancer Institute, Detroit, Michigan

The rationale was to develop recommendations on the use of ¹⁸F-FDG PET in breast, colorectal, esophageal, head and neck, lung, pancreatic, and thyroid cancer; lymphoma, melanoma, and sarcoma; and unknown primary tumor. Outcomes of interest included the use of ¹⁸F-FDG PET for diagnosing, staging, and detecting the recurrence or progression of cancer.

Methods: A search was performed to identify all published randomized controlled trials and systematic reviews in the literature. An additional search was performed to identify relevant unpublished systematic reviews. These publications comprised both retrospective and prospective studies of varied methodologic quality. The anticipated consequences of false-positive and false-negative tests when evaluating clinical usefulness, and the impact of ¹⁸F-FDG PET on the management of cancer patients, were also reviewed.

Results and Conclusion: ¹⁸F-FDG PET should be used as an imaging tool additional to conventional radiologic methods such as CT or MRI; any positive finding that could lead to a clinically significant change in patient management should be confirmed by subsequent histopathologic examination because of the risk of false-positive results. ¹⁸F-FDG PET should be used in the appropriate clinical setting for the diagnosis of head and neck, lung, or pancreatic cancer and for unknown primary tumor. PET is also indicated for staging of breast, colon, esophageal, head and neck, and lung cancer and of lymphoma and melanoma. In addition, ¹⁸F-FDG PET should be used to detect recurrence of breast, colorectal, head and neck, or thyroid cancer and of lymphoma.

Key Words: oncology; PET; ¹⁸F-FDG PET

J Nucl Med 2008; 49:480–508

DOI: 10.2967/jnumed.107.047787

PET is an imaging technique that provides unique information about the molecular and metabolic changes associated with disease. The technology has existed for more than 30 years but has been used clinically for only the last 10–15 years. In this period, dramatic improvements in technology, the routine availability of medical cyclotrons (to produce the necessary short-lived positron emitters), and favorable reimbursement decisions in the late 1990s have led to a tremendous increase in the use of this technology. The major area of clinical application is currently in oncology, with some application in cardiology and neurology.

¹⁸F-FDG PET requires the use of molecules (radiopharmaceuticals) that are labeled with radioactive nuclides. The amount of radiolabeled material administered are extremely small (10⁻⁶–10⁻⁹ g) and have essentially no pharmacologic effect. In this regard, PET has the unique ability to assess molecular alterations associated with disease without perturbing or altering the fundamental underlying molecular and biochemical processes. Although the number of molecular probes that can be radiolabeled with positron emitters is extremely large, and clinical investigational uses number in the thousands, clinical practice has been limited principally to the use of a glucose analog labeled with the positron emitter ¹⁸F-FDG.

¹⁸F-FDG was first synthesized in 1978 (1) and has become the most commonly used radiopharmaceutical for PET studies of cancer and also for the study of normal functions and diseases of the brain and heart. In March 2000, the Food and Drug Administration approved the use of ¹⁸F-FDG to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing methods or in patients with an existing diagnosis of cancer.

Received Oct. 1, 2007; revision accepted Nov. 20, 2007.

For correspondence or reprints contact: James W. Fletcher, MD, Department of Radiology, Indiana/Purdue University, Indiana University School of Medicine, University Hospital, Room 0655, 550 N. University Blvd. Indianapolis, IN 46202-5253.

E-mail: jwfletch@iupui.edu

©Copyright 2008 by the Society of Nuclear Medicine, Inc.

The fact that cancer cells exhibit an increased rate of glycolysis has been known since the 1920s (2), and ¹⁸F-FDG PET is able to assess a fundamental alteration in the cellular metabolism of glucose that is common to all neoplasms. Increased cellular glucose uptake is one of the key alterations associated with the high glycolytic rate of cancer cells.

History

The first medical application of positron emitters was reported more than 50 years ago in 1951 by Sweet at Massachusetts General Hospital (3). This application involved a simple probe that used coincidence detectors to localize tumors in the brain. The first published PET images were acquired using a ring tomograph with the filtered backprojection algorithm and included images of oxygen metabolism with ¹⁵O-oxygen and glucose metabolism with ¹¹C-glucose, as well as ¹⁸F-fluoride bone images (4,5). This publication occurred in 1976, almost 25 years after Sweet’s work at Massachusetts General Hospital.

Significant subsequent advances in PET technology were associated with the identification of bismuth-germanium-oxide as a scintillator material in 1977 (6) and the successful synthesis of ¹⁸F-FDG by Ido et al. at Brookhaven in 1978 (1). The first ¹⁸F-FDG scans were obtained at the University of Pennsylvania in 1979 by Phelps et al. using ¹⁸F-FDG that was synthesized at Brookhaven National Laboratory in Long Island (7–9). The most recent technical innovation, which has been available for only the last few years, is the integration of PET and CT systems. These dual-modality systems offer an advantage over dedicated PET in that they can concurrently provide both metabolic and structural or anatomic images that are automatically fused and overcome some limitations of dedicated PET.

Reimbursement for PET procedures was not available through much of the 1990s, and adoption of the technology was slow. In 1995, the Food and Drug Administration approved ¹⁸F-FDG for brain imaging in patients with epilepsy. This approval paved the way for Health Care Financing Administration reimbursement of PET in January 1998 for lung cancer and cardiovascular disease in Medicare beneficiaries. This coverage was expanded by the Health Care Financing Administration in 1999 to include restricted indications for colorectal cancer, melanoma, and lymphoma. In the following year, the Food and Drug Administration gave broad approval for ¹⁸F-FDG in all cancers and cardiovascular disease.

Near the end of 2000, the Health Care Financing Administration expanded coverage for broad use of ¹⁸F-FDG PET in lung, colorectal, head and neck, and esophageal cancers as well as lymphoma and melanoma. Since that time, indications have been added for breast cancer and thyroid cancer. In February 2006, the Centers for Medicare and Medicaid Services (the new agency name for the Health Care Financing Administration) announced that it would provide coverage for use of ¹⁸F-FDG PET in essentially all other cancers in accordance with its ‘‘coverage with evidence development’’ program. For Medicare beneficiaries undergoing PET as part of this program, referring physicians and PET facilities will be required to provide certain data to the National Oncologic PET Registry to allow for assessment of the impact of PET on intended patient management.

General limitations of dedicated ¹⁸F-FDG PET

There are inherent limitations of ¹⁸F-FDG PET that can result in false-negative and false-positive findings. False-positive findings are most commonly associated with uptake of ¹⁸F-FDG in infectious or inflammatory tissue (10). ¹⁸F-FDG has been reported to accumulate in various inflammatory processes (11–13). Infection imaging with ¹⁸F-FDG PET relies on the fact that granulocytes and mononuclear cells use glucose as an energy source during and only during their metabolic burst (14,15), which takes place when activated by local triggers. It is therefore not surprising that ¹⁸F-FDG accumulates in many types of inflammatory tissue.

For example, ¹⁸F-FDG uptake can be seen in tissue after radiation therapy. Inflammatory changes after radiation therapy can be protracted and a potential source of false-positive findings if the history, timing, and volume of tissue irradiated are not considered at the time of interpretation. ¹⁸F-FDG uptake can vary widely in normal tissue, and regions of discrete uptake in areas such as the ureters, bowel, lymphatic tissue, thymus, brown fat, and muscle—so called normal variants—can be interpreted in error as abnormal or can confound the correct interpretation of the findings.

Mildly to moderately increased ¹⁸F-FDG uptake can also be seen in a variety of benign processes, many of which represent inflammatory or hyperplastic conditions (e.g., villous adenomas, thyroid adenomas, Graves disease, adrenal adenoma, Paget’s disease, and fibrous dysplasia), and familiarity with the behavior of these and other conditions is important in diminishing false-positive results.

Weaknesses of ¹⁸F-FDG PET for cancer imaging include its limited reconstructed spatial resolution of 4–10 mm in available commercial systems. Negative scan findings cannot exclude the presence of a small tumor or microscopic tissue involvement, and precise anatomic localization of the signal can be difficult in certain anatomic regions (e.g., the head and neck). Tumors with a low metabolic rate (e.g., bronchoalveolar carcinoma and mucinous adenocarcinoma) may show minimal uptake of ¹⁸F-FDG, and certain tumors are known to have poor avidity for ¹⁸F-FDG (prostate carcinoma and hepatocellular cancer).

¹⁸F-FDG PET is also generally considered to not be useful in the assessment of possible cerebral metastases from known primary neoplasms. High levels of ¹⁸F-FDG are normally present in the cerebral cortex and substantially limit the utility of ¹⁸F-FDG PET in this application. For this reason, most clinical examinations are of the patient’s torso and include the area from the base of the brain to the mid thigh.

Rationale for the recommendations

The adoption of PET has been variable, but despite limitations in the published literature, ¹⁸F-FDG PET is rapidly becoming an integral part of oncology practice in the United States, Europe, and other countries.

For these reasons, a multidisciplinary expert panel of oncologists, radiologists, and nuclear physicians with expertise in PET/CT convened to develop recommendations on the use of ¹⁸F-FDG PET in oncology practice and to determine the suitability of ¹⁸F-FDG PET in the management of cancer. The multidisciplinary panel was initially convened by the American Society of Clinical Oncology with members from the Society of Nuclear Medicine, American College of Radiology, American Cancer Society, Blue Cross and Blue Shield Association (BCBSA), National Coalition of Cancer Survivorship, US Oncology, and American Society for Therapeutic Radiology and Oncology to evaluate the status of the published literature on PET in oncology and to determine whether recommendations on PET could be developed for referring oncology physicians. The SNM subsequently assumed the responsibility for reviewing and evaluating the outcome of the panel’s efforts and recommendations.

On July 13, 2007, the SNM Board of Directors approved publication of the panel’s findings as this special contribution to the Journal of Nuclear Medicine. Most studies that the panel reviewed included PET without CT augmentation. However, the panel realizes PET/CT use is increasingly common and expects PET/CT to further improve the utility of PET.

The use of ¹⁸F-FDG PET in the following types of cancer was assessed: breast, colorectal, esophageal, head and neck, lung, pancreas, and thyroid cancer; lymphoma, melanoma, and sarcoma; and unknown primary tumor. The goal was to provide practitioners with recommendations on the appropriate use of PET in the management of these cancers and to identify gaps in knowledge that may affect future research. Other neoplasms that have been reported and generally recognized as non–¹⁸F-FDG-avid (e.g., renal, prostate, and hepatocellular cancer) were not addressed.

Two principal questions on the appropriateness of ¹⁸F-FDG PET for the management of cancer were addressed: For what cancers should ¹⁸F-FDG PET be used in clinical practice, and under what specific clinical circumstances should ¹⁸F-FDG PET be used? Recommendations were developed to assist practitioner and patient decisions about health care for specific clinical circumstances (16). It is important to realize, however, that recommendations cannot always account for individual variation among patients. The recommendations are not intended to supplant physician judgment with respect to particular patients or special clinical situations.

Materials and methods

Panel composition

The panel comprised experts in clinical oncology or hematology, radiology or nuclear medicine (specializing in PET), and outcomes or health services researchers with expertise in evidence-based medicine. Both academic and community practitioners were included. A patient representative was also included on the panel.

Process overview

In evaluating evidence on the role of PET, the panel was guided by the process established by the GRADE (Grades of Recommendations, Assessment, Development and Evaluation) Working Group (17). This process follows the principle that systematic reviews of the totality of research evidence represent the scientific foundation for development of clinical recommendations (18,19). Therefore, the panel first attempted to identify all systematic reviews on the use of ¹⁸F-FDG PET oncology and used these to assess the quality of primary research evidence (Tables 1 and 2).

In doing so, the panel soon clearly saw that the systematic reviews themselves were of varying quality and that a separate assessment of the quality of the systematic reviews was required (Table 3). It also became clear that no systematic review was performed using evidence from randomized controlled trials (RCTs). Because, in general, evidence obtained in RCTs is considered the most reliable (17,20) (Table 4), the panel decided to perform an additional search for randomized evidence and perform its critical appraisal. Therefore, the final recommendations were based on the systematic review of available randomized evidence and an overview (systematic review) of the existing systematic reviews addressing clinical indications of interest (Table 5).

Table 1: Definition of grade of evidence for primary studies and systematic reviews

Adopted from recommendations of GRADE Working Group (17).

Table 2: GRADE definitions to assess primary studies

Literature review and data collection

The evidence profiles were distributed to the panel members, who used them during the final panel meeting to make their judgments on the use of PET for each indication.

Pertinent systematic reviews and RCTs from the published literature were retrieved and reviewed for the development of these recommendations. Searches of MEDLINE (National Library of Medicine) and other databases (Institute for Clinical Evaluative Sciences, Blue Cross Blue Shield Technology Evaluation Center, and the NHS Health Technology Assessment Program) for pertinent articles were done using strategies developed by Montori et al. (21) and Mijnhout et al. (22). The search was repeated on June