18F-FDG PET/CT for Image-Guided and Intensity-Modulated Radiotherapy* Eric C. Ford1, Joseph Herman1, Ellen Yorke2, and Richard L. Wahl3 1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland 2Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York and 3Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland Advances in technology have allowed extremely precise control of radiation dose delivery and localization within a patient. The ability to confidently delineate target tumor boundaries, how- ever, has lagged behind. 18F-FDG PET/CT, with its ability to dis- tinguish metabolically active disease from normal tissue, may provide a partial solution to this problem. Here we review the cur- rent applications of 18F-FDG PET/CT in a variety of disease sites, including non���small cell lung cancer, head and neck cancer, and pancreatic adenocarcinoma. This review focuses on the use of 18F-FDG PET/CT to aid in planning radiotherapy and the associ- ated benefits and challenges. We also briefly consider novel ra- diopharmaceuticals that are beginning to be used in the context of radiotherapy planning. Key Words: radiation therapy IMRT IGRT FDG (fluorodeoxy- glucose) FDG PET/CT J Nucl Med 2009 50:1655���1665 DOI: 10.2967/jnumed.108.055780 The tools of modern radiotherapy allow one to control with increasing precision where within a patient a radiation dose is deposited, the intent of which is to irradiate tumor tissue (and areas at high risk of locoregional metastases) while sparing nearby normal tissue. Intensity-modulated ra- diotherapy (IMRT) is currently the most advanced tech- nology available for photons (1���3). IMRT finely tailors dose distributions by exploiting the many more degrees of freedom that are possible with spatial intensity modulation than with more traditional 3-dimensional conformal radio- therapy approaches. Using IMRT in head and neck cases, for example, the radiation oncologist can deliver concave dose distributions that treat large regions of the neck wrapping around the spinal cord and yet can limit the spinal cord itself to receiving a relatively low dose, thus mini- mizing cord damage (2). Also possible are spatially restricted dose distributions that treat tumors in the lung while sparing normal lung and heart, tumors in the brain while avoiding optic nerves and optic chiasm, or tumors in the prostate while sparing the adjacent rectum and bladder (3���7). Several implementations of IMRT are readily avail- able as commercial products (8), and under development are improved approaches such as volumetric arcs, treat- ments in which the whole volume of tumor is treated with a continuous sweep of the gantry around the patient in one or multiple arcs (9,10). Coupled with these advances in dose delivery are new ways of localizing the patient���s tumor and normal tissues during treatment. Although traditional methods rely on laser- based alignment of skin marks supplemented by periodic orthogonal radiographs, a modern radiotherapy clinic can be equipped with stereoscopic kilovoltage radiography capabil- ities or integrated CT guidance that allows precise alignment of patients with respect to the treatment beam (8,11,12). Monitoring patient position and dynamic changes during treatment is also possible with various technologies now available (13���15). This general paradigm of actively using imaging during treatment is referred to as image-guided radiotherapy. Through it, one can approximately halve the residual localization error of the structure defined as the target in the treatment-planning process, as determined with repeated imaging (16). Obviously, the degree to which localization error can be reduced depends on the site being treated, with intracranial tumors representing what is prob- ably a best-case scenario, and a worse case being one with much motion and difficult visualization, such as a gastroin- testinal site. Even with all this technology to precisely control the delivery of a radiation dose, one is still left with the funda- mental problem of determining what region of tissue needs to be targeted. This aspect of designing radiotherapy is often the most challenging. Interobserver variability using CT scans is well appreciated and documented for a variety of common disease sites, including cancer of the lung (17,18) and cancer of the head and neck (19,20), and is caused by difficulty in determining the exact boundary of a tumor, even for expert observers with the best CT protocols. Received Nov. 6, 2008 revision accepted Jan. 28, 2009. For correspondence or reprints contact: Eric C. Ford, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, 401 N. Broadway, Suite 1440, Baltimore, MD 21231. E-mail: eric.ford@jhmi.edu *NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH THE SNM WEB SITE (http://www.snm.org/ce_online) THROUGH OCTOBER 2010. No potential conflict of interest relevant to this article was reported. COPYRIGHT �� 2009 by the Society of Nuclear Medicine, Inc. 18F-FDG PET/CT FOR IMRT ��� Ford et al. 1655

Without an accurate delineation of the tumor region in the first place, precise control of dose distributions may not provide much additional tumor control. PET scans with the radiotracer 18F-FDG may be most useful in this regard. In many common cancers, PET with 18F-FDG, or combined with CT, has greater sensitivity and specificity for disease detection than does CT or MRI alone (21). With its ability to distinguish metabolically active disease, 18F-FDG PET/CT can provide important adjunc- tive information in designing a treatment plan. Figure 1 shows an example case for a patient with pancreatic cancer. In this case, a radiation oncologist has outlined the tumor re- gion based on CT (yellow) and a nuclear medicine physi- cian has outlined the tumor based on 18F-FDG PET/CT (blue). The addition of 18F-FDG PET/CT provides clear evi- dence of disease extending some 2 cm inferior to the boun- dary delineated by CT alone. Although there can be modest misregistrations between PET and CT due to breathing motion (22), this separation between the two regions reflects a real difference between apparent tumor locations on the 2 studies. The present paper focuses on the use of 18F-FDG PET/ CT to improve target definition in IMRT planning. Of course, this represents only one way in which 18F-FDG PET is used in managing the care of cancer patients. Other uses of 18F-FDG PET include better staging of disease to determine whether curative radiotherapy is suitable (23,24) and measurement of treatment response for further manage- ment as used in a variety of disease sites (25���28). Although most cancers are 18F-FDG���avid, some���such as mucinous cancers of the colon, stomach, and other locations���may be less so. Thus, regions for treatment should be drawn with knowledge of the untreated tumor���s avidity for 18F-FDG. This review focuses on disease sites in which tumors are 18F-FDG���avid and for which 18F-FDG PET/CT is currently being most widely used for IMRT planning. We begin with a discussion of several physical imaging issues that apply to nearly all uses of this technology and then discuss each disease site separately. PHYSICAL ISSUES Delineation of Tumor Boundaries One key advantage of 18F-FDG PET in radiotherapy planning is its potential for improving tumor boundary de- lineation. 18F-FDG PET may offer a better indication of the actual extent of disease and may also reduce interobserver variability, thus making treatment volumes more standard over a wide range of physicians and centers, a concept that has been investigated by several authors (17,19,20,29,30). The need for robust delineation of tumor boundaries be- comes even more important in treatment schemes that deliver a dose in relatively few, high-dose (10���30 Gy) fractions, such as stereotactic body radiotherapy, which is being developed to treat the lung (31) and pancreas (32), among other sites. With high-dose schemes, smaller margins are used around the tumor to spare surrounding normal tissue. When smaller margins are used, however, there is less room for error. If the actual tumor is not delineated appropriately, it will fall outside the high-dose volume. In a standard fractionation approach (e.g., 30 fractions of 2 Gy each), large margins of approximately 1 cm are used around the tumor. A standard definition (International Commission on Radiation Units and Measurements, ICRU50) consists of a gross tumor volume (GTV) that is the radiologically appreciable tumor extent, expanded to a clinical target volume to account for micro- scopic extension, and finally to a planning target volume (PTV) to account for various physical uncertainties such as motion during treatment or day-to-day variability in tissue positions. In high-dose schemes, localization is strict and a GTV-to-PTV margin of only a few millimeters is used for example, 2���3 mm would be used for stereotactic body radiotherapy of the pancreas (33) or 5 mm axially for the lung (31). With such strict localization, one must be confident of the accuracy of delineation, and 18F-FDG PET/CT can have an important role in this regard. One must also pay close attention to the technical quality of the PET/CT scan to minimize potential misregistration between the PET and CT images, which are acquired sequentially and not simulta- neously. One aspect of this is respiratory motion. In the delineation of tumor boundaries using 18F-FDG PET, there are several physical imaging issues that likely apply to all treatment sites (34). Foremost is the delineation method itself. There are two challenges to overcome here. The first has to do with the spatial resolution of the PET image, which as used in clinical practice is 7���9 mm after reconstruction with many systems. Even if the distribution of cancer cells were to abruptly end at some location, it would be challenging to identify this edge in the 18F-FDG image given that partial-volume effects will blur the edges. Thus, deriving 1-mm boundaries from a technique with an intrinsically much lower resolution is not expected to be successful. PET excels at identifying the presence of tumor but can fall short at determining the precise margins. Nevertheless, for the purposes of radiotherapy planning, some tumor edge must be delineated. The challenge is to FIGURE 1. Pancreatic adenocarcinoma delineated on CT alone by radiation oncologist (yellow) and on 18F-FDG PET/ CT by nuclear medicine physician (blue). Images are from coronal cut of patient with CT (A) and 18F-FDG PET/CT image fusion (B). Tick marks are 1 cm. 1656 THE JOURNAL OF NUCLEAR MEDICINE ��� Vol. 50 ��� No. 10 ��� October 2009