Reprint

PET/CT in Radiation Oncology: The FROG Manual for Clinical Use 2nd Edition

PET/CT in Radiation Oncology: The FROG Manual for Clinical Use 2nd Edition
Shyam Paryani, MD, MS, MHA John Wells, Jr, MD, MS Larry Wilf, MD Douglas Johnson, MD Walter Scott, MD Anand Kuruvilla, MD Abhijit Deshmukh, MD Sonja Schoeppel, MD Mitchell Terk, MD Tim Jamieson, MD Bruce Tripp, MD Dwelvin Simmons, MD Mark Augspurger, MD Jen Chang, PhD Faye Lazar, CNMT Diane Wolinski Nitesh Paryani Jason Paryani Mitchell Terk, MD April Mendoza, MD Michael Sinopoli, MD Craig Collie, MD David Graham, MD Allison Grow, MD, PhD Brian Thorndyke, PhD

PET/CT and Cyclotron Center of North Florida Florida Radiation Oncology Group Integrated Community Oncology Network OnCURE Medical Corp Jacksonville, Florida

PET/CT in Radiation Oncology: The FROG Manual for Clinical Use 2nd Edition
Chapters: 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Shyam Paryani, MD, Nitesh Paryani, Jason Paryani

2. Basic Principles of PET Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Larry Wilf, MD and Walter Scott, MD

3. PET/CT Simulation & Patient Setup Considerations . . . . . . . . . . . . . . . . . . . . . . .9

Faye Lazar, CNMT

4. Physics & Treatment Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

Jen Chang, PhD

5. Radioisotopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
Diane Wolinski

6. Integrating PET/CT into Fusion Based Treatment Planning Process . . . . . . . . .33

John Wells, Jr, MD, Allison Grow, MD, PhD, Brian Thorndyke, PhD

7. Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Anand Kuruvilla, MD, Craig Collie, MD, David Graham, MD

8. Head & Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47

April Mendoza, MD & Mike Sinopoli, MD

9. Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Sonja Schoeppel, MD

10. GYN Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

Abhijit Deshmukh, MD

11. Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60

Tim Jamieson, MD & Bruce Tripp, MD

12. Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62

Mark Augspurger, MD

13. Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68

Dwelvin Simmons, MD

14. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Shyam Paryani, MD, John Wells, Jr, MD, Mitchell Terk, MD

1. Introduction
Shyam Paryani, Nitesh Paryani, Jason Paryani

The Florida Radiation Oncology Group (FROG) owns or operates thirteen Cancer centers in Northern Florida and Southern Georgia. The group originally started practicing in 1957. There are 19 physicians in the group including 2 dedicated Nuclear medicine specialists. We obtained our first Positron Emission Tomography (PET) scanner in 2001 and have a dedicated GE Minitrace Cyclotron. We implemented the worlds FIRST dedicated mobile PET/Computed Tomography (CT) simulator in 2004. The PETCT unit houses a Siemens Biograph unit (Figure 1). We have since added another mobile Siemens Biograph unit in 2005.

It is vitally important that CTs and PETs be performed in the same anatomic position and co-registered to allow for accurate treatment planning. We have dedicated PET and CT technologists as well as Radiation Therapists that simulate our patients. The PET/CT unit also has external LAP lasers that allow for accurate positioning of patients. The internal lasers in the PET/CT unit are not sufficient enough to allow reproducibility, especially for patients undergoing IMRT (Figure 2).

We have developed a Network Model for our PET/CT and Treatment Planning Center using the CMS system. The PET/CT travels to each of our centers. All routine simulations are performed on the unit. The data is then transferred to each centers Focal Sim Unit. We are able to fuse PET and CTs, CTs with magnetic resonance imaging (MRI), or CTs with previous CTs. The utility of PET along with CT will be discussed in detail in subsequent chapters. The physician then contours the anatomy and outlines the appropriate tumor volumes (GTV, PTV). The data is then electronically transferred to our Centralized Dosimetry center which houses a Broadband Server and two XIO Treatment Planning Systems. Our dosimetry and physics staff devise several alternative plans. These are then transmitted back to the cancer center where the physician can remotely review and compare multiple plans on the Focal Sim. After a plan is selected, the physics team generates quality assurance parameters and appropriate treatment parameters which are transmitted to the appropriate linear accelerator.

The network model has many advantages. Aside from economies of scale allowing us to share the PET/CT scanner with all of our facilities, there are many other cost savings in our treatment planning area. Since all dosimetry functions are centralized, we are able to share personnel, standardize our planning and quality assurance, and decrease the likelihood of errors. For centers with multiple physical locations, we believe that this network is a practical approach which allows us to utilize PET/CT in treatment planning. We will describe our experience with PET/CT in radiation oncology and provide clinical examples on the utility of this modality. We feel strongly that PET/CT is an integral component of any modern radiation oncology department.

2. Basic Principles of PET Imaging: An Overview Larry Wilf, MD, and Walter P. Scott, MD
Until recently, delineating target volumes for the diagnosis, staging, restaging, and treatment of cancer has depended upon anatomic imaging. Computed tomography (CT) and MRI have been the mainstays in this function, as they both provide excellent anatomic detail. Unfortunately, what MRI and CT lack is a measurement of cell metabolism. Historically in our patient practices, we have monitored treatment progress based exclusively upon the change in size and appearance of tumor masses. This surveillance/measurement technique has proven less than optimal, as we have often been handicapped and misled by the poor sensitivity and specificity of this approach. Anatomic imaging leaves us in a quandary when trying to differentiate necrosis, infection, inflammation, and scar from malignancy. Furthermore, size alone cannot differentiate malignant from benign. In the last few years, molecular imaging with F-18 deoxyglucose (FDG)-based PET has altered our imaging schemes with respect to oncologic imaging. What PET (molecular imaging) provides-that anatomic imaging does notis a way to better differentiate benign from malignant lesions as well as follow the changes that occur over time. PET yields a functional imageit tells us what the cells/lesions are doing. Oncologic molecular imaging with FDG-PET is based on the fact that cancer cells often use glucose at a much higher rate than normal cells. PET scanning visualizes this uptake because FDG is an analogue of glucose and is similarly accumulated in metabolically active cells. The increased use of glucose by tumor cells is due to 1) increased rates of the hexose monophosphate shunt, 2) increased hexokinase activity, and 3) increased activity of cell membrane glucose transportation. Metabolic activity is thus positively correlated to FDG accumulation, and when the positron emitted by F-18 annihilates with a nearby electron, two 511Kvp photons are emitted in opposite directions. Ring detectors placed around the patient can triangulate the origin of the annihilation event, and thus image the location of greatest FDG accumulation in the body, down to a resolution of about 4 mm. Because of its unique ability, molecular imaging has proved more sensitive and specific than either CT or MRI for diagnosing, staging, and restaging cancer. In fact, a study by Gambir and coworkers has recently summarized data in more than 26,000 patients and shown that PET was 10 to 20 % more accurate than conventional imaging.1 The major impetus, however, for recent PET expansion into clinical practice has been the ultimate acknowledgment by Medicare and insurance companies that PET not only provides useful new information that the other imaging modalities cannot, but is significantly less expensive than the surgical diagnostic alternatives. PET has thus been shown to be very cost-effective from a patient management perspective.

The major problem with PET imaging alone is the lack of correlative anatomy. The common questions asked of the PET-interpreting radiologist by the referring physician include: Where is that hot spot in the body? What does it correlate to anatomically? Is it a lymph node, bowel, what is it? How can you be sure? PET is inherently limited in resolution, so the ability to align/fuse its images to a more resolved image would seem beneficial. Researchers set out to resolve this problem by linking PET and CT images together, aligned anatomically. This was first accomplished by software systems that would combine the two sets of images from two separate scanners. This process worked reasonably well but was limited by precision, patient positioning, the manipulation of pixel size, DICOM image compatibility, protracted time and effort, etc. Even with these limitations, a PET study fused with a CT study improved the sensitivity and specificity of imaging when compared to CT or PET alone. In order to solve the fusion problems noted above, a team at the University of Tennessee in collaboration with CTI (Knoxville, TN) and Siemens Medical Solutions (Hoffman Estates, IL) developed a dual-modality scanner combining both PET and CT in one unit. This union enabled fusion/overlay to take place more easily as the patient could be scanned by both modalities without moving (only the table moves) between scanners and at the same sitting (not going to two departments, or two locations to accomplish). Furthermore, using CT data instead of transmission scanning data for attenuation correction (a process which minimizes image noise/scatter, improving image resolution) reduced PET scan times dramatically (from 1 hour to 20 minutes per scan). From this point it was easy to see that PET/CT would be, and is, a very useful tool for staging of cancer. From a therapy standpoint, a staging scan (depending upon the tumor type) can help determine who needs radiation therapy alone, chemotherapy alone, or both. Also, if the patient is to receive radiation therapy, the scan can be incorporated into the radiation therapy planning process, particularly useful for patients who are to receive IMRT. Another great benefit from molecular imaging with PET is the ability to determine responsiveness of a tumor or metastasis to the radiation and/or chemotherapy treatment course. PET pharmaceutical uptake/activity/metabolism can be quantified and referenced to a particular patient via Standard Uptake Value (SUV) units. This unique ability allows one to empirically determine the therapeutic response of a given treatment: In other words, is it working, and how much? With PET/CT this question can now be asked and answered often before significant anatomic imaging changes are even detected by routine radiographic testing. The major medical frontier of rapid early response detection can now be crossed. We no longer need to rely solely upon a size change to determine tumor response (Figures 1 and 2). All cancer therapies have side effects that are uncomfortable to the patient and have substantial financial cost. In particular, new chemotherapeutic regimens are extremely expensive and some questionably effective. Metabolic imaging serves a valuable role in the continued evaluation of a particular therapy or treatment program. PET now has a very important role in maximizing the use of effective therapies, and minimizing the use of ineffective

therapies. One can thus see how molecular imaging can function to contain cost. Despite its relatively recent incorporation in daily practice, PET/CT has already shown itself to be an important contributor to the field of Radiation Oncology. Prior to molecular imaging, radiation therapy fields were determined by a CT scan alone that could delineate pathologic masses, but could not accurately determine the amount and extent of smaller tumor deposits. In 2002, a study by Dorendorf concluded that combined PET/CT changed the radiation treatment strategy from curative to palliative 10% of the time. Furthermore, the radiation dose was changed (due to the PET/CT findings) in 30% of the patients, and target volume was altered 40% of the time.2 In summary, we are at the infancy of molecular imaging. PET/CT has become a necessary component of our armamentarium. Having utilized PET/CT imaging routinely for over four years in our practice, no physician in our group would feel comfortable staging, treating, or following our patients without it.

References:
1. Gambhir S, Czernin J. Schwimmer J, et. al. A tabulated summary to the FDG PET literature. J Nuclear Medicine 2001; 42 (5 Suppl): 1S - 71 S. 2. Dizendor, E, et al. Impact of integrated PET/CT scanning on external beam radiation treatment planning (abstract). J Nuclear Medicine. 2002-43 (Suppl): A-118.

Figure 1: Top image: PET/CT scan shows right inguinal non-enlarged lymph node now FDG positive, biopsy proven recurrent lymphoma. Bottom: older, negative PET/CT. Figure 2: Corresponding CT images to Figure 1 8

3. PET/CT Simulation and Patient Setup Considerations Faye Lazar, CNMT

The primary objective in managing cancer with radiation therapy is to deposit enough dose to the malignancy to result in cancer cell death while minimizing the effect on surrounding normal tissue. The treatment planning scan/setup must be performed in a reproducible, accurate, and precise manner to allow optimal definition of the area to be treated. Radiation therapy relies upon medical imaging throughout the treatment process, including the diagnosis, planning, treatment execution, and outcome evaluation for treated patients. Recent advances in instrumentation, as well as advances in computer hardware and software in therapy and medical imaging, have enabled the radiation oncology team to use these tools in a precise three-dimensional format to design customized dose delivery patterns. The ultimate success of radiation therapy is directly related to the effectiveness of the initial treatment planning procedure, and as treatment volumes are tighter and more customized, the importance of daily patient setup and positioning is even more critical. Simulation and Positioning Equipment. CT has been routinely used for treatment planning for several years. CT detects grossly abnormal anatomy that can be identified for targeting, and the density information it provides serves as the basis for patient dose calculation algorithms. PET, as a complementary imaging modality, has recently proven useful in therapy planning and disease monitoring in light of its enhanced ability to discriminate between normal and malignant tissues. The new combined PET/CT scanners provide optimal information for radiation therapy planning. PET and CT data sets are acquired with the patient lying in the same position in one scanning session. The PET data and the CT data are imported into radiation therapy planning systems, allowing the radiation oncology team to have access to both anatomical and functional images that may be accurately fused. The PET data supplements the CT data in that it allows better definition of the target volume. PET/CT ScannerEquipment Considerations. Imaging equipment to be used for radiation therapy planning must be able to duplicate the geometrical, mechanical, and optical features of a radiation treatment unit. The equipment must allow the PET/CT Simulation Technologist (Sim Tech) the ability to position the patient in a position identical to that to be used during the radiation treatment process. With this in mind, a flat surface board similar to a treatment couch should be included when purchasing a combined PET/CT scanner to allow the patient to be scanned in the treatment position. This tabletop should be evaluated for sag or tilt limits before the

purchase is made. The table should have the capability to properly align the patient for the treatmentplanning scan. The bore diameter of the PET/CT gantry should be measuredthe larger, the better. Greater bore diameter allows more flexibility for the use of special patient positioning and immobilization devices during the scanning process. PET/CT SimulationPatient Setup Considerations. External Laser System. In addition to the PET/CT scanner modifications noted above, it is necessary to purchase an external laser system. Laser systems are calibrated specifically to the PET/CT system to align the beams with the isocenter of the unit. Typically 3-4 sources are used to project points of light coinciding with the isocenter. The laser points or lines provide references to align the patient in all three planes-transverse, sagital, and coronal. This critical addition allows the Sim Tech to insure that the references are duplicated on both the planning scan and the treatment unit. Localization Marking Supplies. Appropriate marking tools such as India ink for tattooing and radio-opaque BBs should be kept in the PET/CT scan room. Some patients are set up with marks before arriving, while others will actually be simulated in the PET/CT scanning area. Physician Prescription. Just as a medication prescription is a communication tool between a physician and a pharmacist, the radiation therapy prescription acts as the communication tool between the radiation oncologist and the treatment planning and delivery team. For patients undergoing a planning PET/CT, the prescription should not only include dose parameters, but also relevant information required for patient setup for the treatment-planning scan. The instructions on the prescription should be clear, precise, and complete, and should include exact positioning instructions, contrast requirements, and acquisition parameters. Failure to provide these instructions can result in significant setup errors, useless PET scans, and delayed treatments. The sim tech should be present for the treatment-planning scan, as he or she is the person that best understands the prescription directive written by the radiation oncologist. Patient Preparation. Patients should be prepared prior to their arrival for the PET/CT treatment-planning scan. Exams should be scheduled based on the individual patients physical condition, medications, dietary restrictions and contrast requirements. Immobilization devices should be made in advance, and simulation marks on the patient should be complete before the patient arrives for his scan. The patient and his family should be educated as to the importance of the scan by the physician and therapy technologists in advance. Clear-cut instructions and patient expectations help the patient and his family better understand the process and express their questions and concerns prior to arrival at the PET/CT unit. Instructions should include: Patient preparation for the injection of FDG used for PET imaging (short sleeves or loose-fitting top) Appropriate time(s) to drink oral contrast Appropriate time(s) to take medication such as steroids or Benadryl (when there is concern for a possible reaction to IV contrast)
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 Appropriate time(s) to take sedating medication when needed. Advise the patient to wear comfortable clothing and to remove jewelry at home. Ask the patient to bring any specially constructed immobilization device(s) to be used for positioning during his/her scan. Language, mental status, and anxiety should be addressed before the patient arrives. A friend or family member should be available if needed, and staff members should be sensitive to the patients needs and feelings. Education/Communication. Communication and education affect the level of staff and patient cooperation. Good instructions and rapport ultimately affect accuracy in duplication of the treatment position. The entire interdisciplinary team must communicate from start to finish. PET/CT staff members should be familiar with terminology, anatomy, treatment planning, and implementation of the radiation therapy treatment. The imaging staff should spend time with the therapy staff in the radiation therapy department. They should observe patient setup, planning, and treatment procedures. This will give the imaging staff visual as well as verbal cues needed to properly position the patient using devices and markings specific to that patient. Effective communication leads to successful planning and treatment. Scan and Setup. It is imperative that the treatment planning images be acquired in the exact, precise position that will be used in the treatment process. The success of the treatment program is directly related to this simulation procedure. The PET/CT simulation process varies for each patient depending upon his unique condition, as well as the type and extent of his disease. One of the weakest links in treatment planning is poor patient positioning. If the patient is not comfortable and does not remain still, fancy plans and immobilization devices are rendered ineffective. Spending time with the patient before the procedure, educating and answering his questions, assist him in maintaining a comfortable and reproducible position. Positioning Landmarks. Reproducible patient position is achieved by using a stable surface and landmarks visible on or near the surface of the patient. Initial treatment planning references are appropriately marked using fiducial (skin) marks and orthogonally directed lasers for triangulation. These marks coincide with the projection of external lasers on the skin, and determine the initial and tentative isocenter. Tattoos should be used cautiously, especially when the patient is obese, loses weight during treatment, or has a change in tumor size: These factors can cause the skin to shift in relation to internal anatomy. Immobilization Devices. A comfortable position is used whenever possible to scan and treat the patient. Less movement is likely when a patient can maintain his/her position with minimal or no discomfort. Immobilization devices are often used to help the patient maintain an exact position. The devices should be rigid and durable.

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Immobilization devices fall into three categories: Patient positioning aids, devices that are designed to place the patient in a particular position for treatment. Generally, these devices have minimal structure to ensure that the patient does not move. Simple immobilization devices that restrict some movement, but usually require patient cooperation. Complex immobilization devices that are individualized immobilizers that restrict patient movement and ensure reproductive positioning. Positioning aids are widely available, easy to use, and are used for over a period of time for multiple patients. Head holders are made of formed plastic or polyurethane and come in a variety of heights and contours that allow the proper head and neck angulations and positioning to be achieved. A prone pillow may be used to support the patients chin and elevate the face from the tabletop when the patient is positioned prone. This device may be angled to free the face and forehead from pressure. Foam neck wells, foam cushions, and pillows are used as well for patient comfort. Arm boards are contoured to the shape of the arm and are used to allow the arm to rest comfortably above the patients head and they allow more flexibility in achieving greater arm tilt and extension. Simple immobilization devices are often used in addition to positioning aids. They provide some restriction of movement and stability of treatment position for cooperative patients. The most readily available device is tape such as masking tape or paper tape. Also, plastic or cloth strips with Velcro can be used. Rubber bands approximately 2 cm in thickness can be used to bind the patients feet together: This helps limit hip motion. Other devices include a head frame and bite block system that help maintain chin position and move the tongue out of the treatment area. The bite block can be made of cork, acrylic, Aquaplast pallets, or dental wax. Arm and foot straps are commercially available. Their primary purpose is to pull the patients shoulder out of lateral head and neck fields by having the patient grasp and pull on straps running the full length of the body and around the soles of the feet. Simple immobilization devices are easy to use and costeffective. Several patients can use the same devices over time. Each complex immobilization device is individualized. With such devices, unusual patient positions can be achieved. They can be made of many different products such as plaster, thermoplastics, or Styrofoam. For PET/CT scanning, the mold should be made of a material that does not cause image artifacts. Thermoplastics, made by heating and molding a softened sheet around the body part to be immobilized, are often ideal. Other devices may be made with polyurethane foam produced by combining two chemical reactants in a plastic bag under the body part of interest. The patient is positioned in the treatment position atop this bag and an exothermic reaction takes place. The resultant foam expands around the anatomic structure causing the bag to conform to the shape of the body part, and hardens in approximately fifteen minutes. Regardless of the immobilization device used, it must be available in the PET/CT suite for use in positioning the patient for his scan.
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Use of Contrast Media. Contrast materials help define and isolate anatomical structures and diseased tissues imaged with CT scans. Contrast media visually enhance anatomic structures that would be normally more difficult to see. Commonly used contrast media include barium sulfate (oral) and either ionic or nonionic intravenous contrast media. Of note, treatment-planning systems use tissue density calculations in determining dose deposition when the inhomogeneity correction module is activated. In this instance, it is imperative that contrast-enhanced images not be acquired for treatment planning use. All treatment-planning images should be acquired on the PET/CT unit first, without contrast, and only then a second CT with contrast be obtained for the clinicians use. Before administration of any contrast medium, the patient should be carefully screened for potential reactions or complications. Severe allergic reactions have occurred in some patients requiring emergency intervention. Also, barium sulfate should not be used with a suspected bowel perforation or obstruction. In some cases, gases such as carbon dioxide, oxygen, and air are usedespecially in the rectal area to better define the rectal wall location. Foley catheters are also sometimes used. The catheter balloon is filled with air within the bladder to help define the inferior extent of the bladder. Sometimes the bladder is filled with iodinated contrast to properly delineate structures. In summary, the physician prescription should be followed for patient setup and simulation. The PET/CT acquisition should be acquired with appropriate slice thickness and spacing. Immobilization devices, patient positioning aids, and the laser system must be used to align the patient correctly. Our institution requires that the radiation therapy technologist be present for patient positioning for the PET/CT treatmentplanning scan. The data input from PET and CT images affects accurate planning output. Reproducibility and accuracy determine effectiveness. Quality Improvement. To achieve high standards of patient care, the program for PET/CT treatment planning should continuously be assessed. The goal is to ensure that accurate precise image data is provided and that patients are treated in the highest professional manner. Parameters to be evaluated should include: Quality control of scanning equipment at appropriate times Review of the scheduling process Review of patient preparation protocols Review of treatment-planning instructions and techniques for each therapy clinic; updating therapy and position devices to ensure duplicate devices are available during scanning and treatment Ongoing employee communication and education Assessment of the physical environment of the scan room for order and cleanliness. Total commitment and involvement from all members of the oncologic team are necessary at all times. Complacency and lack of concern are unacceptable in the

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PET/CT simulation and planning environment. Imaging technologists should pursue scientific advancement and should value the role of their profession in this rapidly evolving field. They should be familiar with the multiple facets of imaging therapy and therapy equipment, and how each part integrates with the other to facilitate the patients care. Summar y. The treatment planning process involves an entire oncologic team. The use of PET imaging in addition to CT imaging can optimize the patients treatment planning. At our institution we have found great benefit in incorporating PET scan data into radiotherapy planning. The additional information helps reduce or expand the treatment field size based upon the extent of disease and helps provide better target contouring. We can often use the data to reduce side effects of radiotherapy by constraining normal tissue exposure more confidently, and to better define potential volumes for dose intensification. The radiation therapy process requires all members of the imaging and therapy team to be totally committed to producing accurate, reproducible plans and treatment. The words reproducible, accurate, precise, and effective are used throughout this chapter. All these words apply to every step of setup and simulationfrom the time the decision is made to purchase imaging equipment, to the successful completion of a scan to be submitted to the therapy department. For Further Reading:
Paulino A.C. FDG-PET in Radiotherapy Treatment Planning: Pandoras Box. International Journal of Radiation Oncology 2004; 59: 4, 5. Washington, Charles. Surface and Sectional Anatomy. Principles and Practice of Radiation Therapy. St.Louis: Mosby, 2004 Macapinlac, Hamer,Smith Apisarnthanarax, Thorstad Wade, & Clifford Chao K.S. PET Imaging for Target Determination and Delineation. Practical Essentials of Intensity Modulated Radiation Therapy. Philadelphia: Lippincott, 2005. Dong Lei, Mohan Radhe. Intensity Modulated Therapy Treatment Planning Physics and Quality Assurance. Imaging for Target Determination and Delineation. Practical Essentials of Intensity Modulated Radiation Therapy. Philadelphia: Lippincott, 2005. Leaver Dennis, Keller Rosann, Urisshio Nora, Washington Charles. Simulation Procedures. Principles and Practice of Radiation Therapy. St.Louis: Mosby, 2004. Leaver Dennis, Uricchio Nora, Griggs Patton. Simulator Design. Principles and Practice of Radiation Therapy. St.Louis: Mosby, 2004. Washington Charles, Armstrong Julius. Photon Dosimetry Concepts and Calculations. Principles and Practice of Radiation Therapy. St.Louis: Mosby, 2004. Yap Jeffrey, Carney Jonathan, Hall Nathan, & Townsend David. Image Guided Cancer Therapy Using PET/CT. The Cancer Journal 2004; 10: 221-230. Coleman Annette. Treatment Procedures. Principles and Practice of Radiation Therapy. St.Louis: Mosby, 2004. Yap Jeffrey, Townsend David, Hall Nathan. PET-CT in IMRT Planning. Intensity Modulated Radiation Therapy.

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4. Physics & Treatment Planning Jen Chang, PhD

Introduction. The goal of PET/CT utilization in radiation treatment planning is to provide better delineation of target volumes such that an optimal radiation dose can be applied to the target via conformal radiation treatment. Images obtained directly from the PET scanner, however, do not provide all the necessary information for target delineation; rather, they merely provide information on the distribution of positron annihilation events at the time when the PET scan was performed. Without some understanding of the tracer metabolic pathway, and their respective kinetics, and the limitation of PET technology, it will be difficult to take full advantage of this exciting technology for treatment planning. This chapter will attempt to address concepts of transforming images of annihilation events within organs and tissues into data useful in the radiation treatment planning process. The Histor y of Positron Discover y and Its First Medical Application. In 1928, a young physicist, Paul Dirac, derived a relativistic equation describing the electron. This work led Dirac to predict the existence of the positron, the electrons antiparticle, via his famous Dirac equation. A positron has the mass of an electron but carries a positive charge. When this particle meets an electron, they form an intermediate particle named positronium. This intermediate particle is very unstable and within a very short time (10-7 sec), it annihilates. Its entire combined mass disappears and turns into an energetic electromagnetic wave: two 0.511MeV photons traveling away from the point of annihilation in roughly opposite directions. Carl Anderson later observed the physical existence of this magic antiparticle in 1932, and Diracs prediction of the existence of positrons ultimately led to his being awarded the Nobel Prize in physics in 1933, at the age of 33. The first medical application using positron detection was reported by William H. Sweet and Gordon L. Brownell at Massachusetts General Hospital (MGH) in 19511. Sweet, Brownell, and their physics group developed and built a simple apparatus using two opposing sodium iodide (NaI(Tl)) detectors and coincidence detection circuitry to localize brain tumors. In the same year, Wrenn, Good, and Handler independently described and published their studies of positron annihilation for localizing brain tumors. 2 The Histor y of Positron Emission Tomography (PET). Although the first positron scanner was built in 1950, very limited progress was made to advance its usage in medicine until the 1970s, when the cost of electronic computing became more affordable. The revolution in computer technology was a great boon to PET scanner development: PET scanner design progressed rapidly from a simple 2D detector-array to a complicated 3D detector-array with ring geometry.3-11 In the early 1970s, Chesler of the MGH physics group developed the filtered back projection technique that laid down the groundwork for 3D PET image reconstruction.12-14 As a result, noninvasive 3D quantitative measurement of positron tracer in vivo became possible. Concurrently,

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another parallel revolution was occurring with the development of 3D CT X-ray physics and image reconstruction by Hounsfield.15 Previously, and unrelated to the field of medical imaging, Cormack had published papers in the mid 1960s in which he demonstrated a bench-top x-ray CT scanner with proper image reconstruction based on the Radon equations.16 In recognition of their work in the development of CT scanning, Hounsfield and Cormack were awarded the Nobel Prize in 1979. Cheslers filtered back projection technique for PET was clearly developed in the same time frame as the iterative technique used by Hounsfield and Cormack and is the basis for the current PET image reconstruction algorithm. Together, these two novel bodies of work have been combined to produce modern PET/CT scanning systems.17 For more information on the history of PET and PET/CT development, there are two very informative websites: www.cpspet.com/our_company/history_o_pet.shtml and www.mit.edu/~glb/. The Physics of PET. As noted above, when an emitted positron finally slows down and is attracted by an electron through attractive Coulomb force, they form a positronium. This positronium is very unstable and has a short half-life (10-7 sec). It annihilates and yields two high-energy rays with energy of 0.511MeV each (equivalent to the mass of an electron) and nearly 180o apart (conservation of momentum). These two opposing photons with 180o divergence provide a unique property that enables the quantitation of positrons possible in vivo. Figure 1 illustrates this unique property. The probability that photon 1 will escape from the medium (p1) is: p 1 = e -x (1) The probability that photon 2 (p2) will escape is: p2 = e-(D-x)

(2)

The probability that both photons will escape is the product of p1 and p2: p1 p2 = e-x-(D-x) = e-D (3) where is linear attenuation coefficient. It thus suggests by Equation (3) that it makes no difference where the positron is located inside the body, as all positrons annihilate inside the coincidence detection volume (between the dashed lines) and will have the same probability of being detected. This uniqueness lays down the foundation in using transmission scan or a corresponding CT for transmission correction in PET.

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Figure 1. Schematic diagram illustrates coincidence circuitry, detection volume (between dashed line), and the traveling distance of respective photons.

This unique property makes the intensity level shown on the PET image linear and proportional to the concentration of positron emitting isotope in a particular area of interest. It also allows us to derive important functional information from PET in regard to disease as well as normal tissue. Electronic Collimation. Rather than using a collimator to localize a photons origin, PET uses coincidence circuitry. Each ring detector is paired with several detectors on the opposite side of the ring to increase detection efficiency. Signal output from each pair of detectors is fed into an electronic gating device. The moment that the gating device receives a signal, it opens the gate for a predetermined time window to listen to any incoming signal. If a signal indeed falls into the gating device during this time window (coincidence window), the coincidence circuit will generate a signal and be registered in the counter. The window is usually in the range of a nano-second (10-9 sec), which is derived from D/c (D is the maximum width of the patient body as shown in Figure 1 and c is the speed of light). This timed setting based upon D/c is called the coincidence window. The content of the counter is thus the total number of annihilation events detected within a respective detection volume over time. Collimation by coincidence circuitry is also known as electronic collimation. Positron Range. When a positron is emitted from its parent nuclide, it carries some initial kinetic energy. Table 1 lists commonly used positron emitting isotopes, their halflife, their maximum kinetic energy, and their respective stop distance in water. It is thus foreseeable that the location of annihilation can be at some distance away from the location of its respective emitting isotope, especially where the isotope is in a lowdensity region such as a lung.

17

Parent Nuclide 15 O 13 N 11 C 18 F 68 Ga 82 Rb

T1/2 (min) 2.05 9.9 20.4 109.7 67.7 2.25

EMax ( MeV ) 1.72 1.19 0.96 0.64 1.90 3.35

Stop Distance (mm) 0.7 (3.3) 0.5 (2.1) 0.3 (1.6) 0.2 (0.9) 1.35 (9.0) 2.60 (16.5)

Tab le 1. Commonly used positron-emitting isotopes, radioactive half-life T1/2, maximum positron energy EMax, and distance in water within which 50% (95%) of positrons are stopped.18

Scattering. One major problem in nuclear measurement is due to scattering. Scattering not only changes the vector of the radiation, but also its respective energy. This effect is important in PET scanning, where we are trying to identify the location of positron annihilation. Two kinds of measurement error due to scattering occur: prompt scattering and random scattering. Prompt scattering involves bending of the photon tracks by interactions with matter between the location of annihilation and the detectors. When annihilation occurs, two gamma rays of 0.511MeV are generated with directions of 180 apart. Before the scanner can detect these photons, however, there is a finite probability that one or both photons will interact with traveling medium. Should such an interaction occur, the traveling course as well as the energy of the respective photon will change. Instead of staying on its original course, it will travel a different course as shown in Figure 2. Both photons will be detected at nearly the same time (<D/c, where c is the speed of light and D is the width of medium). Since there is no easy way to know if one or both photons has been deflected, the annihilation event of positron Q might be misinterpreted as happening along the detection volume of BC instead of CC. Random scattering, on the other hand, involves cases of mistaken identity by the ring detectors. The coincidence window will open once it receives a signal from the opposite detector. During that window of time, however, there is a reasonable probability that a photon other than the mate to the initial paired photon from annihilation will hit the detector in the opened window. For example, the detection of one photon from P annihilation and the detection of one photon from R annihilation will be interpreted as an event occurred inside the detection volume of CC. The number of these false events is proportional to the square of the total activity in the body, and it can be estimated through delaying the opening of coincidence windows.

18

Figure 2. Schematic diagram illustrates the misidentifications cause by prompt and random scattering.

As with any nuclear medicine scan, the quality of the PET image is also hindered by limits regarding the maximum radiation dose the patient is allowed to receive. As noted above, the number of true coincidence events can be correctly estimated by the following equations: Transmission correction CTotal = q * CTotal /CTransmission Scattering correction CTrue = CTotal - CPrompt - CRandom where CTotal is the true events if no transmission loss, CTotal is the total measured events, CTransmission is the total detected events in a transmission scan, q is a normalization factor, CTrue is the true coincidence events, and CPrompt and CRandom are the respective events due to accidental prompt and random scattering. To preserve the statistical quality of CTotal , one requires an almost noise-free transmission scan which means a very long scan time for the transmission scan. CT imaging from PET/CT is used to provide an estimate of transmission correction using an analytical formula to not only preserve the image qualities but also to significantly shorten the overall study time. Motion Artifact. Because of the relatively low sensitivity in detection in comparison with CT, the typical scan time for PET is around 2 to 5 minutes per crystal bed time. Unless the imaged organs are stationary, the acquired PET image will be the result of an averaging among images done at different positions. The resultant image of tumor will tend to be larger than it really is, and also its activity distribution will be skewed differently than how the organ moved during the relatively lengthy collection process.

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Treatment planning. CT imaging alone is no longer sufficient for treatment planning of many tumors. Although excellent at helping define anatomy based upon density differences, it provides no physiologic information. In contrast, PET provides unique information about patient physiology rather than anatomy. The development of PET/CT imaging allows the strengths of each technique to be brought to bear for improved target localization and radiation treatment planning. Proper understanding of these imaging modalities, including both their advantages and weaknesses, however, is necessary for proper incorporation into the treatment planning process. Several commonly used isotopes and their respective radiolabeled compounds are listed in Table 2. By selecting a specific labeled compound from the table, one can obtain specific physiological information regarding the tumor status.
E+ I s o to p e
15

R ad i o l ab el e d C o m p o u n d

Proper ty

I n d ic a t o r

CO2 H 2O O2 FDG FLT Fluorothmidine FMISO Fluoromisonidazole FDHT Fluorinated steroid FES Fluoroestradiol Thymidine Methionine Acetate Choline ATSM methylthiosemicarbazone Glucose analog DNA precursor Hypoxic marker Estrogen analog DNA precursor DNA precursor DNA precursor Hypoxic marker

18

11

Cu Cu 64 Cu
60 62

Blood flow Blood flow Metabolic rate for oxygen Metabolic rate Tumor proliferation Tumor hypoxia Estrogen receptor status Tumor proliferation Tumor proliferation Metastases Tumor hypoxia

Tab le 2. Commonly used positron-emitting isotopes, their radiolabeled compounds, and potential applications.

FDG/PET. Glucose is a major source of energy for the body. With the prospect of PET on the horizon, tremendous research efforts were dedicated to synthesizing a positronemitting glucose analogue in the 1970s that could be used to measure the metabolic rate of glucose in vivo. By changing the glucose molecular structure slightly and by specific binding, 2-fluoro-2-deoxy-D-glucose FDG is created19 (Figure 3). This FDG mimics standard glucose transport from plasma to tissue, where it can then be phosphorylated to FDG-6-phosphate by the same enzyme (hexokinase) that changes standard D-glucose to D-glucose-6-phosphate. While D-glucose-6-phosphate continues on the path of glycolysis, the metabolic process of FDG-6-phosphate cannot continue

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because of the change at #2 carbon position (Figure 4). FDG-6-phosphate is trapped in tissue. It is the trapping of this metabolic product of FDG in tissue that makes the measurement of glucose utilization in tissue possible.20 Thus, after FDG injection, detectable positron emission occurs based upon: a) free FDG in the vasculature b) free FDG in tissue, and c) trapped FDG-6-phosphate as shown in Figure 5 The latter is most important for our purposes, but correcting for the free FDG floating about can be problematic. To help resolve this issue, compartmental analysis is helpful and provides insights into the ratio of FDG-6-phosphate (signals) to free FDG in vasculature and in tissue (background noise).

Figure 3. The molecular structure of 2-fluoro-2-deoxy-D-glucose (FDG). Note that the 18F was labeled specifically on #2 carbon position (TRIUMF, University of British Columbia).

Figure 4. Diagram illustrates the metabolic pathway from D-Glucose to D-Glucose-6-phosphate and then to D-Fructose-6-phosphate. Note that the #2 carbon position, pointed by red arrow, is where phosphoglucoisomerase acts on. .

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Figure 5. Compartmental model used to describe FDG transport between plasma and tissue. C*P (t), C*E (t), and C*M (t) represent concentration of FDG in plasma, in tissue, and FDG-6-phosphate in tissue. k*1 ,k*2 ,k*3 , and k*4 are rate constants governing the transport of FDG and FDG-6-phosphate between compartments.

After FDG injection, the rate of change for 18F as free FDG and trapped FDG-6phosphate can be expressed by the following two equations:

For a steady physiological state, with stable rate constants from the time of FDG injection to the time of scan, the amount of trapped FDG-6-phosphate will be a good measure of the metabolic rate of glucose with respect to the particular region of interest. However, PET can only measure the total positron annihilation events (C*Total (t)) in a tissue:

Therefore, to have measurements that are physiologically meaningful, one needs to determine the best time (T) that will yield excellent signal-to-noise ratio,

As the metabolic rate of tumors may be very different from normal tissue, optimal scan start- and stop-times providing the best noise-to-signal ratio may vary from one type of tumor to another. Indeed, recent published studies, as well as our own experience, have suggested that the tumor may be better delineated in certain settings if the scan is scheduled at a time later than 60 min after initial FDG injection. More studies are needed in this area.
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Tumor delineation. PET has been used for treatment planning of brain, head and neck, lung, esophageal, cervical cancers, and others, as will be described elsewhere in this publication. It is used to delineate not only the primary malignancy but also to help identify regional spread of tumor requiring incorporation into treatment fields. Before the commercial combined PET/CT scanners were available, tumor delineation was done either through refined sophisticated image fusion algorithms with treatment planning software or through hand-eye coordination by looking at corresponding PET and CT images at the same time. With mechanical co-registration between CT and PET datasets on modern combined units, the CT and PET images obtained at the same time are automatically co-registered and coded at their respective image header. Any software that is capable of reading the image header, doing the necessary image manipulation, and generating two sets of images (PET and CT) with mating pixel size, slice thickness, and slice location, can be used to bring PET into the radiation oncologists daily practice. This software capability allows contour drawing on one set of images to be automatically duplicated onto the other set of images and vice versa in a linear fashion. One of the major benefits in using PET/CT for radiation treatment planning is its ability to provide better target delineation. Nevertheless, difficulties and pitfalls exist. The scatter phenomena described above add some geometric uncertainty (up to 4 mm in soft tissue or to 1 to 2 cm in region with low density such as lung) as to the exact origin of the positron annihilations. In addition, simply defining and standardizing abnormal uptake is problematic in itself. There are several approaches to characterize the extent of tissue FDG uptake. SUV and SUVg (SUV normalized to plasma glucose level) measurements are widely used. However the relatively large variation of SUV among individual study subjects and over various time intervals makes these valuations suspect. Measuring regional metabolic rates for glucose consumption has also been used for characterizing the target. This procedure, however, requires continuous sampling of FDG in arterial blood, which makes the method impractical in an average clinical setting. Other clinicians simply use the display intensity to delineate the target volume. Caution is in order, however, as the intensity level can be manipulated easily through the display threshold and window level, enlarging or shrinking target volumes at the touch of a button. Clearly, much work remains to be done in this arena, as no simple method of PET-based target delineation has yet been developed. In the meantime, most users opt to err on the side of larger fields with good margins, doublechecked with CT anatomic information, and solid clinical judgment.

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References
1. Sweet W.H.; The use of nuclear disintegration in diagnosis and treatment of brain tumors; New England Journal of Medicine, 1951; 245:875-878. 2. Wrenn Jr. F.R., Good M.L., and Handler P.; The use of positron emitting radioisotopes for localization of brain tumors; Science, 1951; 113:525-527. 3. Robertson J.S., Marr R.B., Rosenblum M., Radeka V., and Yamamoto Y.L.. 32-Crystal positron transverse section detector, in Tomographic Imaging in Nuclear Medicine, Freedman GS, Editor. The Society of Nuclear Medicine; New York; 1973, pp.142-153. 4. Phelps M.E., Hoffman E.J., Mullani N.A., Ter-Pogossian M., Application of Annihilation Coincidence Detection to Transaxial Reconstructed Tomography, Journal of Nuclear Medicine; 1975, 16;210-215. 5. Phelps M.E., Hoffman E., Mullani N., Higgins C., Ter-Pogossian M.; Design considerations for a positron emission transaxial tomograph (PET III). I.E.E.E. Trans. Biomed. Eng.; 1976, NS-23:516-522. 6. Hoffman E., Phelps M., Mullani N., Higgins C., Ter-Pogossian M.; Design and performance characteristics of a whole body transaxial tomograph. J. Nucl. Med.; 1976; 493-503. 7. Cho Z.H., Chan J.K., and Eriksson L.; Circular ring transverse axial positron camera for 3-dimensional reconstruction of radionuclide distribution. IEEE. Trans. Nucl. Sci.; 1976, NS-23:613-623. 8. Derenzo S., Budinger T., Cahoon J.; High resolution computed tomography for positron emitters. I.E.E.E. Trans. Nucl. Sci.; 1977, NS-24:544-558. 9. Brownell G.L., Burnham C.A., Chesler D.A., Correia J.A., Correll J.E., Hoop Jr. B., Parker J. and Subramanyam R.; Transverse section imaging of radionuclide distribution in the heart, lung and brain; Reconstruction Tomography in Diagnostic Radiology and Nuclear Medicine, 1977, pp.293-307.3. 10. Eriksson L., Bohm C., Kesselber M., Litton J-E, Bergstrom M, Blomquist G.A.; A high resolution positron camera. In: Greitz T., Ingvar DH, Widen L., eds. The metabolism of the human brain studied with positron emission tomography; New York: Raven Press, 1985, 33-46. 11. Huesman, R.H., Derenzo, S.E. and Budinger, T.H., A two-positron sampling scheme for positron emission tomography in Nuclear Medicine and Biology, Ed. Raynaud C. Pergamon Press: New York. 1983, pp.542-545. 12. Chesler D.A.; Three-dimensional activity distribution from multiple positron scintigraphs; Journal of Nuclear Medicine; 1971, 12:347-348. 13. Chesler D.A.; Positron tomography and three-dimensional reconstruction technique in Tomographic Imaging in Nuclear Medicine, ed. Freedman GS., The Society of Nuclear Medicine: New York. 1973, pp.176-183. 14. Chesler D.A., Hoop Jr. B., and Brownell G.L.; Transverse section imaging of myocardium with 13NH4, Journal of Nuclear Medicine; 1973, 14:623. 15. Hounsfield G.N.; Computerized transverse axial scanning (tomography). Part I: Description of system. Part II: Clinical applications, British Journal of Radiology; 1973, 46:1016-1022. 16. Cormack A.M.; Representation of a function by its line integrals, with some radiological applications, J. Appl. Phys.; 1963, 34:2722-2727; (also) Cormack A.M.: Reconstruction densities from their projections, with applications in radiological physics, Physics in Medicine and Biology 1973, 18:195-207. 17. Townsend DW, Beyer T, Kinahan PE, Charron M, Dachille M, Meltzer C, Brun T, Jerin J, Byars LG, Nutt R. [Eds. Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K] Recent studies with a combined PET/CT scanner. In: Positron Emission Tomography in the Millenium. Elsevier, 2000;229-244. 18. Levin, C.S., Hoffman E.J.; Calculation of positron range and its effect on the fundamental limit of positron emission tomography system spatial resolution. Phys Med Biol 44:781-799. 1999. 19. Ido T., Wan C.N., Casella J.S. et al.; Labeled 2-deoxy-D-glucose analogs: 18F labeled 2-deoxy-2-fluoro-Dglucose, 2-deoxy-2-fluoro-D-mannose and 14C-2-deoxy-2-fluoro-D-glucose. J. Labeled Compds. Radiopharmacol, 1978:14:175-183. 20. Sokoloff L., Reivich M., Kennedy C., Des Rosiers M.H., Patlak C.S., Pettigrew K.D., Sakurada O. and Shinohara M.. The [14C] Deoxyglucose Method for the Measurement of Cerebral Glucose Utilization: Theory, Procedure and Normal Values in the Conscious and Anesthetized Albino Rat. Journal of Neurochemistry, 1977, Vol. 28, pp.897-976.

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5. RADIOISOTOPES Diane M. Wolinski, Director, North Florida Cyclotron Center, LLC

Introduction. An ever-increasing variety of clinical applications of PET in the areas of oncology, neurology, and cardiology has encouraged recent increased production of existing and novel radiotracers and radiopharmaceuticals. Several routinely produced radiopharmaceuticals are readily available in the United States for relevant PET and PET/CT scans, allowing assessment of glucose metabolism, hypoxia, neuroreceptor mapping, blood flow, and unique research applications. Glucose metabolism, in particular, is used in the diagnosis, staging, and post-therapy evaluation of oncology patients.13 A listing of those radiolabelled compounds currently used in research, cardiology and neurology shall be mentioned herein; however, the focus of this chapter will be the background and use of the most common radiopharmaceutical manufactured to date. Although novel radiotracers continue to be developed to further unique applications in the fields noted above, the vast majority of clinical usage to date continues to lie in oncology, utilizing the most widely used PET radiopharmaceutical, 2 (fluorine-18) fluoro-2-deoxy-D-glucose (18F-FDG), commonly known as FDG. More recently, sodium fluoride F 18- injections have been requested for bone scans of select patients. Background. We will focus mainly on the use of FDG in PET imaging for oncology patients. Although available for research uses over decades, the use of FDG-based PET scanning did not become popular until its approval for reimbursement by the Center of Medicare and Medicaid Services (CMS)previously known as the Healthcare Finance Administrationin the year 2000, when it adopted national coverage policies for several [18F]FDG PET procedures related to specific cancers.7 [18F]FDG PET is a radiolabeled analog of glucose that rapidly travels throughout all organs of the body. It is transported into the cells and phosphorylated at a rate proportional to the rate of glucose utilization within specific tissues. The radiopharmaceutical cannot exit the cell once phosphorylated by the enzyme hexokinase until it is subsequently dephosphorylated by glucose-6-phosphatase. There is a delicate balance of retention and clearance of FDG between these mechanisms. Changes in this balance between FDG transport and phosphorylation are used to measure and assess glucose metabolism in the organs or tissues. Accelerated glucose metabolism has been recognized as a cancer recognition tool for years, but is not specific to cancer. FDG was initially used as a tracer to study brain and heart metabolism. Only later, after several independent studies in the 1980s, did FDG PET imaging become an obvious tool for cancer imaging.8 Specifically, regions of decreased or absent uptake of FDG signify decreased or absent glucose metabolism relative to surrounding organ or tissue background activity. Conversely, increased uptake in a specific area suggests increased glucose metabolism. In cancer cells, glucose metabolism variations detected by FDG accumulation may be quite extreme:

25

FDG accumulation may increase, decrease, or remain normal depending upon the type of tumor, its stage of development, and its location. Additionally, glucose metabolism utilizing FDG in biological tissue can identify other cellular dysfunction. For example, it has shown promise in neurological conditions such as epilepsy, dementia, and Alzheimers disease. In cardiology, FDG may be useful in identifying patients likely to benefit from myocardial revascularization.1 Other applications for FDG will be mentioned later in this chapter. Description. As noted previously, FDG is the common name for the radiopharmaceutical, 2 (fluorine-18) fluoro-2-deoxy-D-glucose (18F-FDG). It is known commercially as Fluorodeoxyglucose F18 Injection, USP, a positron-emitting radiopharmaceutical containing radioactive 2-deoxy-2-[18F] fluoro-D-glucose: usually abbreviated as [18F]FDG , or simply FDG. The isotope is administered via rapid intravenous infusion. This isotonic drug is packaged in a sterile, pyrogen-free, multipledose glass vial, with a pH range of 5.5 to 7.5, is preservative-free, and is a clear, colorless solution. Its half-life is 109.8 minutes with the molecular formula C8H1118FO5, and its molecular weight is 181.26 daltons.3 According to the United States Pharmacopeia (USP), it contains not less than 90.0% and not more than 110.00% of the labeled amount of 18F expressed in MBq (mCi) per mL at the time indicated in the labeling. It may contain suitable preservative and/or stabilizing agents. Additional information regarding packaging, storage, and labeling may be found in the current USP.3 Man ufacture . Producing recovered 18F from an aqueous solution of (H2O/18F-) is achieved by proton bombardment of enriched water, (18O), in a GE Medical Systems MiniTrace cyclotron, utilizing a nuclear reaction, 18O(p,n)18F, and finally is extracted by ion-exchange chromatography using a synthesis unit such as a GE Medical System MX. It can then be solvated organically and, through nucleophilic substitution, specifically combined into radiopharmaceutical applications. Essentially, it is manufactured with nucleophilic substitution of [Kryptofix 2.2.2]18F with the corresponding protected precursor. Mannopyranose, in the form of its trifluoromethansulfonyl analogue, is used as the precursor for the preparation of FDG. In our cyclotron center, the final step of acid hydrolysis produces the final product, although a base hydrolysis method can also be used. The corrected radiochemical yield runs consistently around 65% of the initial F-18 activity. A full process production run encompasses approximately 3 1/2 hours. Step one, F-18 production, may typically take from 30 to 130 minutes dependent upon the final FDG radiopharmaceutical required for the day. Step two, post F-18 delivery to the synthesis unit and the synthesis itself, is completed in approximately 32 minutes. Quality Control. Currently, all compounds like FDG that carry a radioisotope used for PET imaging require Food and Drug Administration (FDA) approval.14 Appropriate criteria and procedures to evaluate PET products for safety and effectiveness are still under discussion. Under section 505(b)(2) (21CFR 355 (b)(2)) of the FDA

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Modernization Act (FDAMA) signed in 1997 by the President, the FDA believes it could currently support the approval of some commonly used PET radiopharmaceuticals. The USP testing methods for FDG are the only current testing standards recommended. A battery of quality-control tests is referenced in the Pharmacopeia within the official monograph for FDG injection. These tests include radionuclide identification of a gamma-ray spectrum at 0.511 MeV and a possible reflective peak at 1.02 MeV. Its halflife is listed as a range of 105 to 115 minutes. A chromatogram of the product solution shall be not more than 10% of a prepared standard. No more than 175/V USP endotoxin unit per mL of the Injection is contained at expiration time. The listed pH is 4.5-8.5, although the more practical values range from 5.5 to 7.5. Radiochemical, isomeric, radionuclidic, and chemical purity tests shall be performed in addition to the total assay for radioactivity listed as MBq or mCi per mL. A post-release sterility test (14 days duration) shall be performed.3 Drug Handling and Disposal. Prior to administration, the vial is visually inspected for discoloration and particulate matter. It must be disposed of in a safe, compliant manner within applicable nuclear regulations if the drug has indication of unsuitability or visual contamination. Suitable garments are worn to protect hands and eyes, and appropriate protective shielding for 511 keV gamma exposure is used. The specific gamma ray constant for fluorine F 18 is 6.0 R/hr/mCi (o.3Gy/hr/kB) at 1 cm. The half-value layer (HVL) for the 511 keV photons is 4.1 mm lead (Pb). For example, the interposition of an 8.3 mm thickness of Pb, with a coefficient of attenuation of 0.25, decreases external radiation exposure by 75%. Needless exposure to technologists, patients, and other nearby persons is to be avoided. Only employees with appropriate training in radionuclide handling, including physicians, technologists, and ancillary personnel who are approved by the appropriate agencies to use these radionuclides, shall be in proximity to the drug. Administration. Preparation of the patient by prior instruction should include discussion of the effects of fasting, varying blood sugar level, glucose intolerance, diabetes, activity and exercise prior to PET scan utilizing FDG; proximity to children/pregnant women post injection; notification of pregnancy or possible pregnancy; liquid intake (to hydrate the patient prior to drug administration); and other instruction by the physician or nurse as indicated. A measurement of blood glucose level immediately prior to the injection is an important part of the process to assure minimal adverse reaction of the patient due to the fact that this isotope is, generically speaking, radioactive sugar water. The FDG is typically administered as a unit dose injection of 10 to 15mCi calibrated at injection time. The optimum time for a PET scan is usually achieved 30 to 40 minutes after injection.4 Utilizing the current technology of the PET/CT scanner, the typical whole-body scan utilizing the radiopharmaceutical FDG will be complete in less than 30 minutes, exclusive of preparation time. For most procedures, a single scan is required for acquisition. However, in evaluating pulmonary nodules or assessing mediastinal adenopathy, a second scan may be requested by the physician.10 The second

27

procedure does not require a second injection of the radiopharmaceutical, as the FDG continues to circulate throughout the body several hours after injection.11 FDG is eventually cleared from most tissues within 24 hours, and eliminated in the urine. Drugdrug interactions and overdoses have not been reported.6 Limitations. FDG PET does not work equally well for all tumors. Indications for the most effective use of PET are evolving. Although FDG is the most commonly used tracer for cancer imaging, there are some well-known limitations to its use. These include effective limits of resolution of approximately 5 mm in size, inability to consistently differentiate between inflammation and malignancy, difficulty visualizing brain tumors, and difficulty visualizing intra-pelvic tumors hidden behind the bladder.9 False-positive and false-negative results may occur in some instances. Inflammation/inflammatory cells may indicate a false positive PET result due to increased FDG uptake.5 Similarly, fungal infections and benign tumors with patterns of increased glucose metabolism may result in false-positive exams. A negative result does not preclude the diagnosis of cancer. FDG competes with glucose for uptake in tissues. Some tumors have low uptake and are not detectable, as with prostate cancer. Furthermore, FDG is excreted by the kidneys to a much greater extent than glucose due to lower renal re-absorption of FDG than glucose. Diabetic patients can therefore have low FDG uptake in tumors if their serum glucose levels are high. If proliferation rate imaging is desired, FDG may not be the best option due to its comparable uptake to the cell cycle.12 Lastly, the drugs half life is a short two hoursits usefulness is therefore limited by the need for daily on time production and mandatory rapid delivery just prior to injection time. It is literally a race against the clock to synthesize the radiopharmaceutical, FDG, once the F-18 is produced, and get the patient injected. Therefore, the cyclotron center and the PET/CT unit should be in relatively close proximity to take full advantage of the synthesized product. Other applications of PET radiopharmaceuticals. Promising applications for PET may lie within the fields of neurology and cardiology. FDG is increasingly utilized as a tool in evaluation of neurodegenerative conditions as well as in diagnosis and management of these disorders. In the brain, early clinical intervention after the positive diagnosis of Alzheimers disease via FDG-based PET imaging is possible. Brain tumors may be located and distinguished from scar tissue, and a more accurate assessment in tumor and other sites in the brain suitable for delicate surgery may be achieved. A myriad of investigative tools including FDG is used to identify focal epilepsy, refractory epilepsy, and Parkinsons disease. Other conditions such as fronto-temporal dementia (FTD), primary progressive aphasia (PPA), semantic dementia (SD), progressive prosopagnosia (PP), and progressive visuospatial dysfunction (PVD) may have altered FDG uptake as well. In the heart, PET may be beneficial in mapping out appropriate heart surgery bypass fields after a myocardial infarction. Prior to an infarction, PET can quantify the extent of heart disease.2 Using N-13 ammonia, qualitative and quantitative regional coronary blood flow and metabolism can be measured. Dysfunction, via the absence of ongoing metabolism correctly measured by PET, should be considered the primary standard of
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myocardial viability detection.1 Sodium fluoride F18- injection is indicated in PET as a useful tool in imaging patients with osteogenic sarcoma ie, a malignant bone cancer.15 Bone scan tomography with 3D whole-body imaging using the PET/CT scanner produces a superior image to other imaging modes. It may be useful in assessing bone perfusion, regional bone pathology, or metastatic disease in the skeletal system. Current Positron Isotope Production. Four basic positron-emitting radionuclide compounds are currently produced for use in PET imaging studies, include oxygen -15, nitrogen-13, carbon-11, and fluorine-18. Fluorine-18 is most popularly produced by proton bombardment of enriched water (18O) utilizing a nuclear reaction, 18O(p,n)18F, producing recovered 18F from an aqueous solution of (H2O/18F-) and finally extracted by ion-exchange chromatography. It can then be solvated organically and, through nucleophilic substitution, utilized in radiopharmaceutical production. An alternate method of production using electrophilic substitution resulting in a radioactive gas is rarely performed.1 Fluorine-18 decays by positron emission. The principal photons useful for diagnostic imaging are the 511 keV gamma photons produced by positron annihilation resulting from the interaction of the emitted positron with an electron. Radiopharmaceuticals using this tracer and their usefulness in biomedical application include: [18F]FDG (glucose metabolism), [18F]FMISO (hypoxic tissue), [18F]MPPF (serotonin 5HT1A receptors), [18F]A85380 (nicotine acetylcholine receptors), [18F]FLT (DNA proliferation), [18F]FUdR (nucleic acid metabolism), [18F]mustard (hypoxic tissue), and [18F]nitroisatin (caspase-3 inhibitor).13,14 Nitrogen-13 is produced by proton bombardment of distilled water (16O) utilizing a nuclear reaction, 16O(p,)13N. To minimize in-target oxidation, a scavenger such as ethanol may be used. There is no further chemistry involved in its production. Radiopharmaceuticals using this tracer and their usefulness in biomedical application include: [13N]ammonia (myocardial blood flow).1 Carbon-11 is produced by proton bombardment of natural nitrogen through the nuclear reaction on 14N(d.n)15O. Oxygen -15 can be produced as molecular oxygen (15O2) by mixing the target gas with 5% natural carbon dioxide as a carrier, or directly as carbon dioxide (C15O2). By reduction of C15O2 on activated charcoal at 900C, carbon monoxide (C15O) can also be easily produced. A great limitation of this isotope is its relatively short half life (t 1/2 =20 min.). Theoretically, with 11C, any organic molecule could be labeled by isotopic substitution of 11C for natural carbon, retaining the full properties of the parent molecule. Unfortunately, the short half-life of this radioisotope creates limitations: The multi-step synthesis processes to create the radiopharmaceuticals end with a low yield of product for the effort. Radiopharmaceuticals using this tracer and their usefulness in biomedical applications include: [11C]SCH23390 (dopamine DI receptor), [11C]flumazenil (central benzodiazepine receptor), [11C]PK11195 (peripheral benzodiazepine receptor), [11C]PIB (amyloid plaque: Alzheimers disease), [11C]AG1478

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(EGF receptors), [11C]choline (biosynthesis of phospholipids), [11C]methionine (amino acid metabolism/brain, head/neck, lung, breast, prostate, urinary bladder tumors), [11C]tyrsine (amino acid metabolism/brain tumors (C11-tyrosine), [11C]5HTP (serotonin levels/neuroendocrine gastrointestinal tumors), [11C]L-DEP (monoamine oxidase B enzyme levels/pituitary tumors), [11C]L-DOPA (dopamine levels/neuroendocrine pancreatic tumors), [15C]O2 (blood flow/brain tumors), [15C]O (blood volume/brain tumors), [11C]AG957 (BCR-abl receptors).13,14 Oxygen-15 is produced by deuteron bombardment of natural nitrogen through the 14 N(d,n)15O nuclear reaction. Molecular oxygen (15O2) production or direct production as carbon dioxide (C15O2) can be produced via mixing target gas with 5 percent natural carbon dioxide as a carrier. Additionally, carbon monoxide (C15O) can be produced easily by reducing carbon dioxide (C15O2) on activated charcoal at 900C. 15O2 - oxygen can be directly produced out of the target without further chemistry. Radiopharmaceuticals using this tracer and their usefulness in biomedical applications include: [ 15O]oxygen (oxygen metabolism/brain tumors), [15O]carbon monoxide (blood volume/brain tumors), [15O]carbon dioxide (blood flow), [15O]water (H215O) (blood flow).13,14 Investigational Isotopes and Potential Applications. Researchers are designing new radiopharmaceuticals as innovative solutions to todays limited PET imaging applications. One of the difficulties of expansion of products is the relative short half-life (some only minutes in duration) of many proposed drugs. Additionally, there does not appear to be a universal PET radiopharmaceutical suitable for all types of tumors in the field of oncology, nor for cardiology or neurology applications. However, the study of research-level investigational isotopes continues to push forward the horizons of novel applications. Although limited studies and evaluation of patients utilizing the following radioisotopes and radiopharmaceuticals have been performed to date, continued collection of data from larger patient studies is critical to the development of appropriate radioisotopes for future drug approvals. A limited list of research-grade tracers follows. Additionally, the use of sodium fluoride F18- has been used as an imaging agent in the study of patients to define areas of altered osteogenic activity. So d i u m F l u o r i d e F 1 8- . The active ingredient in sodium fluoride is sodium [18F] fluoride, also know as Na[18F]F, with a molecular weight of 41 grams/mole. It typically contains 9 mg of sodium chloride and a calibrated amount of sodium [18F] fluoride. Its decay is similar to FDG with a positron emission and half-life of 110 minutes. The principle 511keV gamma photon (produced from interaction with an electron) is useful in diagnostic imaging. In bone scans, the fluoride ion passes into the hydration shell surrounding each bone crystal from the plasma and is taken up in bone in proportion to blood flow and bone metabolic activity. Since skeletal uptake of the [18F]fluoride ion is altered in areas of abnormal osteogenesis, visualization of osseous lesions is possible.16,17 The greater deposition of F18- accumulates in the skeleton symmetrically in the axial region, the bones around joints, fracture site, and in bones affected by fibrous

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dysplasia, osteomyelitis, Pagets disease, spondylitis tuberculosis, hyperostosis frontalis interna, tumors, myositis ossificans, and ephiphyses.18,19 Less accumulation occurs in the shafts of long bones and appendicular skeleton.
Radiotracer
18

Applications
18

F-Fluoromisonidazole ( FMISO)

hypoxia/brain tumors, ischaemic penumbra/stroke1 sequential cerebral blood-flow studies, oxygen consumption, cerebral profusion quantification in ischaemic stroke, quantification of brain function, parietal lobe function, working memory processing1 qualitative/quantitative regional coronary blood flow in evaluation/coronary artery disease1 (recently approved for production - limitation of short half-life) quantify cerebral benzodiazepine receptors/psychiatric, panic, traumatic stress disorders1 brain tumors, ovarian cancer, prostate cancer, metastisis to pelvic lymph, bones 9

H215O , 15O2, and C15O2

13

N-ammonia

11

C-flumazenil

18

F-Fluorocholine

Summar y. The use of FDG PET has had a considerable positive effect on the management of oncology patients. PET has demonstrated its usefulness as an imaging modality if utilized for specific applications with select patients. In spite of its current limitations, metabolically active diseases can be tracked using this tool. As new radiotracers are developed, and as approval for their use becomes more widespread, it is clear that the ability to image and manage additional cancer types will broaden the scope of PET imagings utility.

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References:
1. http://www.austin.unimelb.edu. PET Clinical Applications. 08/07/03. 2. http://www.petscan.org/about.cfm CancerSource. 05/25/05. 3. United States Pharmacopeia & National Formulary. USP 24.NF 19. 2000. 4. PETNET Pharmaceuticals, Inc. Product information. 2002. 5. Houn, F.1999: Review of [18F]FDG PET in the Evaluation of Malignancy. 6. Jones, S.C., Alavi, A., Christman, D., Montanez, I., Wolf, A.P., and Reivich, M. The Radiation dosimetry of 2-F-18 fluoro-2-deoxyglucose in Man. J.Nucl. Med. 1982;23, 613-617. 7. CMS Decision Memorandum 2000. #CAG-00065N, 2002 Memorandum #AB-02-065. 8. Warburg, O. The Metabolism of Tumors. New York: Richard R. Smith Inc. 1931:121-169. 9. Hara, Toshihiko, MD, PhD. Dept. of Radiology.18-F-Fluorocholine: A new Oncologic PET tracer. J.Nucl.Med:2001:42:12, 1815-1816. 10. Mathies, Alexander MD, Hickeson, Marc MD, Cuchiara, Andrew, PhD, Alavi, Abass, MD. Dual Time Point 18FFDG PET for the Evaluation of Pulmonary Nodules. J. Nucl. Med: 2002:43:7, 871-875. 11. Lodge, MA, Lucas, JD, Marsden, PK, Cronin, BF, ODoherty, MJ, Smith, MA. A PET study of 18-FDG uptake in soft tissue masses. Eur. J. Nucl. Med. 1995:36:883-887. 12. Wahl, RL, Harney J. Hutchins G, et al. Imaging of renal cancer using positron emission tomography with 2-deoxy2-(18F)-fluoro-D-glucose: pilot animal and human studies. J Urol Dec 1991:146(6):1470-1474. 13. Hani A. Nabi, MD, PhD, Jose M. Zubeldia, MD. Clinical Application of 18F-FDG in Oncology. J Nucl Med Technol 2002: 30:3-9. 14. Minnesota Dept. of Health. Positron Emission Tomography (PET) for Oncologic Applications. Executive Summary. 1999. www. Health. State. Mn.us/htac/pet.htm 15. http://www.scid.org/encyclotpedia/Osteogenic_Sarcoma International Society for complexity, information, and Design. 16. Moon NF, Dworkin HJ, LaFluer PD. The clinical use of sodium fluoride F 18 in bone photoscanning. JAMA 1968 Jun; 204(11):116-22. 17. Tse N, Hoh C, Hawkins R, et al. Positron emission tomography diagnosis of pulmonary metasteses in osteogenic sarcoma. Radiology 1996 Jul; 200(1):243-7. 18. The skeletal system. In: PDR Physicians desk reference for radiology and nuclear medicine. Oradell, NJ: Medical Economics Company; 1978.p. 66. 19. van Dyke D, Anger HO, Yano Y, e al. Bone blood flow shown with F-18 and the positron camera. Am J Physiol 1965; 209(1):65-70.

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6. Integrating PET/CT into Fusion-Based Treatment Planning Process John Wells, Jr. MS MD, Brian Thorndyke, PhD, and Allison Grow, PhD, MD
In an era when radiation oncologists routinely try to restrict CTs/PTVs/treatment volumes in order to minimize toxicities and escalate dose, prudence mandates constant efforts to minimize PET/CT simulation errors as well as straightforward methods to contour PET/CT volumes. This chapter focuses on three factors which we consider important in the development of PET/CT fusion based treatment planning programs. They are scanner setup, education of the PET/CT staff regarding proper patient positioning/scanner settings, and dosimetric rules for contouring PET-defined volumes of interest. Scanner Setup. It is important to use the scanners flat board insert. Patients scanned on a concave couch and treated on a flat table are at risk for uncorrectable setup errors. In addition, it should be noted that small pitch deflections can occur when the concave scanning couch is fully extended. By strengthening the couch this effect is minimized. The scanners internal fixed lasers can be used to define isocentric entry points. However, when your patients isocenter needs to be near the surface, the internal lasers may be rendered useless as it may be impossible to shift the couch to bring the internal lasers to bear. In addition, based on the patients size and surface topography, it may be difficult to visualize and mark the three isocentric entry points. Solutions to this problem may be achieved by marking and placing BBs on the patient at the time of traditional or CT simulation prior to PET/CT scanning, or through the use of an external laser system (we use Lap Link) focused on the scanner to generate the three isocentric landing points. In our practice, we use our Lap Laser system to mark the patients isocentric entry points after which BBs are placed and the patient immediately scanned. Prior to leaving the room, it is important for the CT tech to zero the couch on the isocenter. Failure to so do may create treatment plan display problems. When PET/CT scans are being processed for use in treatment planning, one should ensure that the PET slice count equals the CT slice count by using a transformed image set. PET/CT staff should be instructed to provide you with this data set which will ensure proper coregistration of images for planning purposes. When the PET and CT images are acquired on the same scanner (eg, Siemens Biograph PET/CT, or GE Discovery ST PET/CT), it is assumed that the patient has remained in the same position throughout both scans, and thus the PET and CT series can be coregistered automatically based on DICOM coordinates. To ensure that the PET and CT slice counts are the same, a transformed data set should be requested. If

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the PET and CT are performed on different scanners, which we do not recommend, then PET/CT registration must be performed manually, either through visual inspection of PET images superimposed on CT, or by identifying landmarks and applying corresponding software translations and rotations. Finally, whether fusion is hardwareor software-based, one can always affix radio-opaque PET fiducials to the patient to provide additional verification of PET/CT alignment prior to contouring. Patient Positioning Instructions. Unless you are fortunate enough to have a PET/CT scanner in your department, your planning scan will be performed outside of your department down the hall or down the street. In the later two situations, it is important to educate the facilitys staff prior to asking them to perform your scans. Their nuclear medicine and/or CT backgrounds do not prepare them for radiation oncologys precision positioning requirements. In our experience, it is best to send a dosimetrist to the procedure to make sure the study is correctly performed. While minor variations in roll, pitch, and yaw are not important from a diagnostic perspective, they are critical to ours as it is impossible to correct for these errors on the planning computer. The dosimetrist assistance in the placement of treatment aids such as masks, molds, straps, foot braces, etc is invaluable. Prior to leaving the PET/CT room before scanning, the dosimetrist should check the isocentric marks/BBs one last time to make sure they neither wash nor fall off prior to treatment. Contouring Recommendations. We do not view PET-derived volumes as precise representations of targets of interest. We use the coregistered CT for this. We use PET-derived volumes to minimize our geographic miss risk during large field planning, and to maximize the benefit of field reduction by staying on target as fields are reduced during treatment. All modern planning systems can vary the blending of the coregistered PET and CT. When contouring PET positive regions, we set the blender bar on our CMS focal contouring stations to PET only to optimize the visual display.

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With respect to contour itself, we recommend that you draw your margin 4 to 5 mm beyond the visible border of the PET positive site you want to contour. This fudge factor accounts for limits of resolution due to photon non-colinearity, which is in the range of four mm. Since a clump of 1 million cancer cells can fit on a pinhead, while they might contribute photons that enhance the visualized border you see, by itself, this clump will not visualize. Ergo, our fudge factor. As an aside, we draw our fields based on traditional CT-based field design which has been modified to include PET data as we are concerned about geographic misses by planning only PET positivity. Future Development. In the next few years, automated SUV-based contouring systems will come on the market that should significantly reduce contouring time. These applications will likely rely on minimum and maximum thresholds to determine PET volumes within a region of interest, similar to currently available algorithms for autosegmenting CT structures. There are additional hurdles for PET segmentation, however, since radiotracer activities (whether absolute or SUV-normalized) characterizing a malignant lesion are not well established. Indeed, it may be the case that the appropriate threshold for a given malignancy is site-, stage-, and patient-specific. Some research involving mouse models has suggested it may be fairly accurate to delineate an 18FDG-PET volume by selecting all neighboring voxels with an intensity approximately 40% to 50% of the lesion maximum (see Maxim P, Thorndyke B, et al, IJROBP vol. 63, p. S490), although the precise cutoff appears to vary with tumor size. Clearly any robust auto-contouring algorithm for PET will require sophisticated statistical and physiological modeling, which will become available as data is increasingly accumulated from manual PET/CT based contouring.

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7. LUNG CANCER Anand M. Kuruvilla, MD, FACRO, A. Craig Collie, MD, David W. Graham, Jr., MD
Introduction of PET/CT scanning into the radiation oncologists armamentarium has begun to play a major role in todays therapeutic interventions for lung cancer. In almost two thirds of patients analyzed in one study, PET/CT scanning influenced treatment intent, modality, and delivery by either upstaging or down staging the patients (36/56=64%), or by influencing the final treatment volume (22/34=65%).1 Enhanced PET/CT based staging has resulted in a near doubling of median survival times in non-small-cell lung cancers (NSCLCa) due to stage migration seen with more accurate patient staging, and subsequent treatment with radical radiation therapy alone or in combination with chemotherapy.2 Bradley, et. al. from Washington University recently reported FDG PET/CT altered AJCC TNM Stage in 31% and altered the radiation therapy volume in 58% of the patients studied.3 CT-based 3D conformal radiation treatment planning in lung cancer is based upon the excellent imaging of lung and mediastinal structures where both tumor and normal tissues are well delineated anatomically. Most importantly, CT provides electron densities of the relevant tissues, with which radiation therapy planning software computes dose distribution. Current generation scanners that combine the two modalities, use the CT component for PET attenuation correction, in addition to localization. Most NSCLCa patients will require a combined modality treatment plan including radiation therapy and chemotherapy, with or without surgery. We make every attempt to facilitate early consultation with both medical and radiation oncologists during the initial staging work-up. Such early involvement and coordination is imperative to facilitate needless duplication of effort, and allows staging procedures such as the PET/CT to be done in the treatment position, so that the data collected can be used not only for staging, but also for direct input into the radiation therapy treatment planning system. Appropriate consents are obtained during the initial consultation. The patient then undergoes a pre-simulation process. Typically, patients are placed in a supine position on the simulation couch (fl at table) with arms overhead, and the simulation technologist then fabricates a comfortable immobilization device, (Alpha cradle) which is able to readily fit into the PET/CT bore. After reviewing the relevant available diagnostic imaging studies, the radiation oncologist fluoroscopically encompasses the areas involved as well as the adjacent echelons at risk, with generous margins. The radiation oncologist also takes this fluoroscopic opportunity to crudely but relatively effectively visualize the extent of normal motion on the relevant structures. While in the standard simulator, anterior and lateral laser points (at d1/2) are marked with indelible markers and covered with Tegaderm. AP and lateral orthogonal films centered on these points are taken through the region of interest.

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Next, the patient is taken to the PET/CT suite and positioned on a flat scanning couch. Ideally, the PET/CT couch should be equipped with the same LAP lasers that are in the simulation and treatment suites, to ensure reproducibility and consistency of patient set up. To facilitate this, the simulation technologist assists the PET/CT technologist in the set up of the patient in a manner that geometrically mimics the parameters in the simulation and treatment suites. Prior to whole-body PET/CT, bb markers are placed on the orthogonal marks noted above for the CT portion of the scan, and are subsequently replaced by FDG markers for the whole-body PET study that typically scans from the base of skull to the midthighs. The non-contrast planning chest CT uses 3 mm slice thickness scans from the level of the hyoid superiorly to L1/L2 interspace inferiorly to ensure the lung bases are imaged. Recently, an additional delayed PET/CT scan protocol is performed one hour after the first PET/CT to unmask potentially involved nodes; increasing SUV uptake in these nodal groups on the delayed study is considered to signify involvement (Figures 1 and 2). It is expected that inclusion of these nodal groups in the treatment portals will reduce the risk of geographical misses. Following completion of the study, the radiation oncologist reviews the combined study with the diagnostic radiologist, who in our case is also a nuclear medicine physician, to clarify pathologic involvement. SUVs that compare FDG uptake of tissues of interest to normal liver SUV levels are particularly useful (SUV levels higher than background liver is suspicious for tumor involvement). The combined review is symbiotic as getting feedback on the clinical history enables the radiologist to generate a comprehensive report while the radiation oncologist learns normal artifacts that could otherwise easily be mistaken and contoured as tumor FDG uptake; brown fat in the supra clavicular area or mediastinum can easily be mistaken for metastatic lymph nodes or learning to differentiate muscle uptake from neoplastic. The mediastinal lymph node stations at risk will obviously depend on the primary site of origin. The diagnostic radiologist can also help the radiation oncologist differentiate normal vasculature and mediastinal contents from pathologic areas. With time and experience, radiation oncologists can quickly develop the expertise to manipulate the intensity threshold of PET fusion images brought into the radiation therapy treatment planning system software, to help with tumor-volume contouring. One typically starts contouring with the images at 40% of maximum intensity to help delineate the GTV and distinguish tumor from atelectasis and obstructive pneumonitis. Even with PET/CT, however, this is definitely not an exact science, and we will often overestimate a volume rather than risk a geographic miss. GTV treatment volumes today typically include the FDG-avid primary tumor and nodal volumes. In addition, any nodes enlarged by CT criteria (> 1 cm) are included in the clinical target volume (CTV). Typically a 1 to 2 cm Planning Target Volume (PTV) margin is extended beyond the CTV to further prevent geographical misses, and even more volume is included as needed to allow for respiratory motion. Of interest, the fact that the PET image is acquired over several minutes ensures that the hot spot of uptake representing the primary tumor will incorporate a volume through which the tumor

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moves throughout several respiratory cycles. This allows the physician to be more confident of the true volume of tissue requiring treatment by contouring the FDG-avid areas and thereby accounting for a large component of the 3D respiratory motion (see case presentation in Figures 3A-3E). The challenge in treating lung cancer has always been how to safely increase the tumor dose while minimizing normal tissue irradiation. Additionally, the focus today is to achieve full doses of chemotherapy to be administered concomitantly with radiation. IMRT lung irradiation helps facilitate this end by reducing esophageal irradiation while at the same time keeping the spinal cord, cardiac and lung volumes within tolerance limits. Gating technologies are maturing but are far from being perfected. We have recently been using PET/CT images with our planning software to determine the extent of motion artifact. The following protocol is employed: The initial PET/CT scan is completed, 45 minutes after FDG administration; subsequently, in selected cases, a second delayed PET/CT study is performed one hour later, through the chest bed position only. This free breathing study is done with the patient instructed to breath normally, i.e., with tidal breathing and no breath hold. Two final chest CT studies with limited breath holds are then performed: 1) in Inspiration and 2) in Expiration Our techs pre-counsel patients well during the preparation period and we find most patients can maintain a limited breath hold for 10-15 seconds during each scan. The radiation oncologist typically will pick the delayed CT to be the primary set for treatment planning. The delayed CT and delayed PET scan are then transformed, which is really the process of co-registering their distinct origins within Siemens Biograph e.soft software. This process essentially locks these two DICOM image sets so that they are accurately and reliably fused and are then imported into our planning software. The CT is imported as the primary DICOM data set while the PET is the secondary DICOM data set. As described earlier, now the radiation oncologist contours the Gross Tumor Volume (GTV) on each axial CT image, while constantly referencing the PET image. This volume is called the free breathing GTV. Once this is completed, the PET scan is discarded and the free breathing primary CT is then fused to the Inspiration CT (which now replaces the PET data set as the secondary data set) and GTV Inspiration is then contoured on each axial image and finally, the last GTV expiration set is contoured when the CT expiration is fused to the free breathing CT using the above described methodology. Figure 4A & 4B shows these three GTVs that encompass the tumor surrounded by a planning tumor volume (PTV). We currently use this methodology to attempt to gauge the extent of respiratory motion and determine the extent of the margin of PTV to use.

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Tumors move in all dimensions, up and down, in and out, and also undergo twisting distortion. Chest wall, diaphragm, and mediastinal extension does limit some of the motion, but with the advent of 4D imaging technologies it is evident that these movements can still be quite substantial. Multiple vendors are coming out with gating solutions but, in the interim, we are using the above methods in carefully selected patients with IMRT particularly when it is clear that the IMRT dosimetry in these situations is far superior to any 3D conformal option. Table 1 outlines the guidelines used by the FROG with regards to normal tissue doses and volumes when doing an IMRT plan for lung cancer.4,5,6,7 The radiation oncologist assesses the extent of motion in each case during treatment planning to assess feasibility and typically the dosimetrist attempts to generate the best 3D conformal plan in each case that is compared to the IMRT plan to verify the benefit of using IMRT in the case. Figures 5A - 5D are images pertaining to a 61-year-old lady with a 6 cm non-small-cell lung cancer involving the superior segment of the left lower lobe, Stage II B, T3 NO MO per PET/CT and treatment with concomitant chemoradiotherapy as she was medically inoperable. Low-dose weekly Carbo/Taxol was delivered with IMRT to 5940 cGy. The initial volume included the lingular chest wall primary tumor, with left hilar and mediastinal nodal echelons at risk and her treatment included a 5-beam IMRT plan in 25 fractions. Primary and nodal regions both received 180 cGy per day. After the initial 45 Gy and radiation was continued to the GTV alone with 3 IMRT beams with an additional 1440 cGy in 8 fractions. The main advantage with this approach is that, in addition to sparing the heart, spinal cord, and protecting her normal lung, the patient had minimal esophagitis during treatment and could complete the prescribed course with no interruption. Studies may eventually prove the relative safety of higher doses, but we still currently prescribe 60 to 66 Gy as the norm. Recent results of the RTOG 9311 dose escalation study with 3D CRT, with or without neo-adjuvant chemotherapy only, noted that the radiation dose could be safely escalated to 83.8. Gy for patients with the V20 < 25% and up to 77.4 Gy with the V20 between 25 to 36%.8 8 The majority of non-small-cell lung cancers today require concomitant chemoradiotherapy. Already there is reliable data becoming available that the best results attainable today will be with full doses of chemotherapy with concomitant irradiation. 9 We now have the tools in our armamentarium to help our patients achieve this end.

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Figure 1. 58-year-old male presented with a cough. Imaging demonstrates 8 cm right apical paravertebral mass.

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(A)

(B) Figure 2. Standard PET/CT imaging acquired 45 minutes after FDG administration does not show any FDG activity in the mediastinum (A), whereas delayed scan 1 hour later does reveal mediastinal FDG uptake indicating involved mediastinal lymph nodes (B).

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Figure 3A. 80-year-old medically inoperable patient with poorly differentiated squamous-cell carcinoma of the bronchus intermedius. Mediastinoscopy was negative. PET/CT confirmed right infrahilar FDG-avid mass (maximum SUV 15.2) with associated right lower lobe segmental atelectasis posterior to the central mass. One hour delayed imaging also confirmed lack of FDG-avid mediastinal nodes.

Figure 3B. Image demonstrates ability of PET to delineate FDG avid tumor from atelectasis, thereby providing an opportunity to minimize normal tissue irradiation.

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Figure 3C. The patient was treated concomitantly with radiosensitizing carboplatin and Taxol along with 5-field IMRT using 6MV photons. Prescribed tumor dose was 63 Gy in 35 fractionations. Note: 1) the esophagus is protected, enabling the patient to tolerate combined modality treatment without interruption due to esophagitis, and 2) IMRT treatment facilitated by PET/CT imaging allows the high radiation dose to wrap around the spinal cord.

Figure 3D. To protect lung function, beam arrangements are selected to limit a maximum of 22% of the lung to 20 Gy. Attempts are made to minimize cardiac irradiation and injury as well.

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Figure 3E. Post-treatment PET/CT 1 week following radiation treatment demonstrates near-complete resolution of abnormal FDG uptake. In light of good response, current chemotherapy regimen was continued for another 2 cycles.

PTV (outer dark red) GTV Inspiration (green) GTV Free Breathing (yellow) GTV Expiration (pink) Nodal Volume (blue)

Figure 4A: Stage III A, right upper lobe adeno carcinoma with FDG avid enlarged right para tracheal nodes also questionable FDG uptake in right scalene seen on delayed scan. Axial composite of free breathing CT, showing GTV free breathing (yellow) contoured from fused PET data set, GTV inspiration (green) from fused inspiration CT set, GTV expiration (pink) acquired from fused expiration CT, contoured nodal volume (from fused PET) and finally a 1 cm PTV, encompassing all GTVs.

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Figure 4B. Anterior DRR showing PTV (red) encompassing GTVs acquired from free breathing (yellow), inspiration (green) and expiration (pink) CTs and blue nodal volumes at risk. Patient treated with IMRT 45 Gy prescribed preoperatively with concomitant Carbo/Taxol. At resection: 2 of 15 mediastinal nodes contained metastatic cancer. Patient then received an additional 15 Gy to the mediastinum with concomitant chemotherapy, followed by 2 additional cycles of full-dose chemotherapy.

Figure 5A. PET/CT demonstrating T3 N0 M0 (Stage II B lesion).

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Figure 5B/C. Axial CT with fused free breathing, expiration and inspiration GTVs demonstrate minimal movement encompassed by PTV. DRR to right depicts primary tumor treated to 59.4 Gy and nodes to 45 Gy.

Figure 5D. DVH demonstrates primary 59.4 Gy, nodes 45 Gy, spinal cord < 40Gy, lungs V20 < 37%, esophagus V55 < 30%.

Sug g ested Tar g et and Normal Tissue Doses: Lung Cancer GTV: Gross tumor from PET &/or CT. CTV: Uninvolved nodes included at discretion of radiation oncologist, accounting for concomitant chemotherapy, specific disease location and extent, and pre-treatment lung function. Typically, CTV may only be about 2 cm beyond the furthest involved nodal station. PTV: CTV + 0.51 cm. Dose to PTV: from -7% to +15%. Normal Tissue Tolerance Doses Lung: V20 < 37% of total lung volume. (total lung volume = volume of both lungs minus PTV, and V20 is volume receiving > 20 Gy). Strive to keep individual Lung V20 < 22 %. Spinal Cord: Global max and dose at any point not to exceed 40 Gy. Contour entire vertebral canal as cord, and than add a 1 cm margin, which is what we define as cord plus 1 cm. This rule should not be violated. Esophagus: V55 should be < 30%. Mean esophageal dose < 32 Gy. Note: Contour entire esophagus from larynx to G.E junction. Hear t: V50 should be < 40%. Whole heart < 40 Gy. 6 Me v P h o t o n s u s e d w i t h c o r r e c t i o n f a c t o r s u n l e s s o t h e r w i s e s p e c i f i e d Tab le 1. Suggested target and normal tissue doses for lung cancer. 46

8. Head and Neck Cancer April Mendoza, MD, and Michael Sinopoli, MD
Introduction. Primary head and neck cancer can arise from anywhere in the mucosal lining of the upper aerodigestive tract. Squamous cell carcinoma is the most common histology and is often associated with tobacco and alcohol use. For many years, radiation was reserved for locally advanced and unresectable tumors. More recently, with an increased focus on functional outcomes and organ preservation, radiation with or without concurrent chemotherapy is considered the standard of care for many subsites. Due to extensive lymphatic drainage pathways, head and neck cancers tend to metastasize to regional nodes in somewhat predictable patterns. PET imaging can greatly help in identifying metastatic lymph nodes, as well as the extent of the primary lesion. Initial Staging. Clinical staging of cervical lymph nodes is fraught with error. Palpation, CT, and MRI have historically over-, or under-staged patients up to 25% of the time. PET staging decreases that margin of error to less than 10%.1 The sensitivity of PET for accurately staging cervical lymph nodes ranges from 82% to 88% and specificity from 94% to 100%. This is a marked improvement over CT and MRI with sensitivities and specificities of 65% to 88% and 41% to 47%, respectively.2 Detection of the primary site is accurate in 88% to 98% of cases, and in cases of metastatic cervical nodes from an unknown primary, PET can reveal an otherwise clinically undetectable lesion in up to 20% of cases.3 One significant advantage of PET over other imaging modalities is the ability to stage a primary lesion and regional nodes, while simultaneously searching for distant metastases and a possible synchronous primary lung cancer. Treatment Planning. Radiation treatment planning for head and neck cancer typically involves obtaining CT scans or radiographs with the patient positioned in appropriate immobilization devices such as thermoplastic masks. The ability of newer generation PET/CT scanners to acquire complete whole-body scans for both staging and treatment planning in a single setting within 20 minutes greatly enhances patient comfort and convenience. Fused anatomic and metabolic images are invaluable for GTV delineation during the treatment planning process. IMRT is often utilized in head and neck cancer for maximal normal tissue sparing. Parotid sparing is of primary importance in minimizing chronic xerostomia and improving quality of life. By utilizing PET/CT fusion, one study demonstrated concordant GTV volume in 89% of patients based on clinical and conventional imaging compared to PET activity in the primary site. This allowed maximal parotid sparing in 71% of patients where there was no PET activity near the parotids.4 Another study demonstrated that PET/CT data were critical in altering the radiation treatment plan in 31% of patients compared to traditional imaging. The majority of the changes were due to upstaging of the primary or detection of cervical metastases.5

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Future trends in molecular- and hypoxia-targeted therapy will utilize metabolic scanning to select targeted systemic therapy or guide higher-dose regions in radiation treatment fields. Fused Cu-ATSM PET/CT images have been utilized to plan IMRT integrated high dose boost regions within hypoxic areas of primary head and neck tumors. 6 Response to Treatment. The optimal utilization and timing of post-treatment PET/CT scans for evaluation of response and prediction of outcome has yet to be defined. Several studies have demonstrated that pretreatment SUV values correlate with disease-free survival, with high values predictive of worse outcome.7 The use of PET CT for detection of residual disease or recurrence has a high sensitivity but moderate specificity due to false-positive readings at sites of post-surgical or post-radiation inflammation. Timing of the follow-up scan has a significant effect on accuracy. The most accurate window for detection of true residual or recurrent tumor appears to be between three and four months after completion of radiation. PET evaluation of residual lymphadenopathy following radiation or chemoradiation is valuable in identifying patients who may avoid a neck dissection. Post-treatment PET at 12 weeks follow-up had a negative predictive value of 100% in one study, with no local failures in necks with residual detectable nodes but negative PET scans which were observed without salvage neck dissection.8 Conclusion. PET/CT imaging is an important and effective tool in the diagnosis, staging, treatment planning, and follow-up of head and neck cancer. Pre-treatment PET/CT identifies the location and extent of disease, and post-treatment PET/CT response has been shown to correlate with outcome. Furthermore, it helps select patients with residual cervical nodes who may forego neck dissection. PET/CT definition of radiation treatment volume allows for dose escalation within the tumor volume using IMRT integrated boost technique. Future integration of hypoxic or molecular imaging will further refine target definition and normal tissue sparing in head and neck cancer.
References. 1. Adams S, Baum R, Stuckensen T: Prospective comparison of 18 F-FDG PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head and neck cancer. Eur J Nucl Med 25:1255-1260, 1998 2. Kau RJ, Alexiou C, Laubenbacher C: Lymph node detection of head and neck squamous cell carcinomas by positron emission tomography with flourodeoxyglucose F 18 in a routine clinical setting. Arch Otolaryngol Head Neck Surg 125:1322-1328, 1999. 3. Fogarty GB, Peters LJ, Stewart J: The usefulness of fluorine 18-labelled deoxyglucose positron emission tomography in the investigation of patients with cervical lymphadenopathy from an unknown primary tumor. Head Neck 25: 138-145, 2003. 4. Nishioka T, Shiga T, Shirato H: Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas. IJROBP 53: 1051-1057, 2002. 5. Ha PK, Hdeib A, Goldenberg D, Jacene H, Patel P, Koch W, Califano J, Cummings CW, Flint PW, Wahl R, Tufano RP. The role of positron emission tomography and computed tomography fusion in the management of early-stage and advanced-stage primary head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 132:1216, 2006. 6. Chao KS, Bosch WR, Mutic S: A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. IJROBP 49:1171-1182, 2001 7. Greven K. Positron-emission tomography for head and neck cancer. Sem Rad Oncol 14:121-129, 2004. 8. Yao M, Smith RB, Graham MM, Hofman HT, Tan H, Funk GF, Graham SM, Chang K, Dornfield KJ, Menda Y, Buatti JM. The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. IJROBP 63:991-9, 2005.

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9. Breast Cancer Sonja Schoeppel, MD

Introduction. Breast cancer is the most common cancer in women, accounting for one third of all cancer cases among women in the United States and causing approximately 40,000 deaths annually1. Accurate staging of disease extent is a major determinant of appropriate treatment recommendations. PET/CT is a Medicare-approved indication for the initial staging and follow-up of patients with breast cancer. It is a more sensitive and specific identifier of malignant tissue in the breast than CT or MRI .2-4 In addition, a recently published retrospective blinded study comparing 1) PET/CT, 2) CT alone, 3) PET alone and 4) side-by-side PET and CT, proved that PET/CT was significantly more accurate in assessing the extent of disease (local tumor burden, lymph node involvement, and distant metastasis) than either modality alone or side-by-side5. This chapter will explore the uses of PET/CT in the clinical practice of radiation oncology pertaining to breast cancer management. First, a brief overview of breast cancer imaging will be performed. Next, the benefits and indications for PET/CT for breast cancer patients will be discussed. Finally, case studies of the use of PET/CT in radiation treatment planning will follow. Breast Cancer Imaging. Mammography remains the mainstay of imaging for breast cancer screening. In patients with known breast cancer, it helps determine the extent of disease locally. This information in turn helps the clinician decide whether local treatment by lumpectomy with radiation is adequate, or whether mastectomy is required. Ultrasound and breast MRI are complementary imaging modalities. Although tremendously important, all these modalities suffer from one main limitation: they only look at the breast itself, and can only discern structural anomalies. Because PET/CT imaging screens a much broader area of the body, and can often detect metabolic abnormalities before structural changes even occur, PET and PET/CT represent a great complement to existing local imaging modalities. Although it cannot replace screening mammography due to sensitivity and cost issues, PET/CT can be very helpful diagnostically for women with dense breasts or with abnormal axillary exams. Before the era of PET/CT, our patients with locally advanced breast cancers were initially staged with CT scans of the chest, abdomen, and pelvis, and a bone scan. Because PET/CT is more sensitive and specific than CT alone, and only slightly less sensitive than a bone scan, we currently stage these patients with PET/CT and bone scan. Our PET/CT scanner also performs F-18 bone scans. This approach not only allows one stop-shopping for the patient, but may well also result in cost savings over time to the healthcare industry by reducing the number and variety of tests ordered.

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Radiation Por t Design: the Influence of PET/CT. PET/CT is primarily used in the radiographic work-up of breast cancer when disease outside of the breast is suspected. Patients who are found to have positive lymph nodes by sentinel node biopsy or axillary dissection are most likely to benefit from PET/CT staging. Nodal metastasis in the supraclavicular, internal mammary, and mediastinal regions are more reliably identified by PET/CT than other imaging modalities including mammography, ultrasonography, MRI, and CT6. As noted above, mammography, ultrasonography, and MRI are all limited by their field of view. These modalities and CT are also unable to identify metabolically active cancerous tissue. Defining the extent of nodal involvement is crucial for therapeutic decisions. For radiation oncologists, it dictates the extent of the radiation fields. Obviously, if radiation fields do not adequately cover disease, the likelihood of local regional control is substantially diminished. Case study #3 illustrates a recurrence at the margin of standard radiation fields of the chest wall. We now routinely use the PET/CT data to help design the extent of our radiation ports for both the chest wall and regional lymph node areas. Patients with breast cancer involvement of their lymph nodes are also more likely to have distant metastasis. If distant metastasis is identified, therapeutic recommendations change markedly. In some cases, the aggressiveness of local treatment may be reduced to allow greater emphasis on addressing disease at other sites. Therefore, as the most sensitive, specific, and accurate method of identifying metastasis, the PET/CT scanning should be incorporated routinely into the staging procedure. It should be noted, however, that PET/CT has limitations. Breast cancer is a spectrum of diseases. Some histological variants of breast cancer are more indolent than others and take up FDG less avidly than more metabolically active tumors. Lobular breast cancer, for example, usually shows a lower uptake than invasive ductal carcinoma (7). Another PET/CT pitfall revolves around infection or inflammation: patients may have abnormal uptake in normal breast tissue from inflammatory processes such as mastopathy or post-surgical healing. Despite these limitations, PET/CT is a useful tool for staging and follow up of breast cancer patients.

Case Studies.
Case #1. Patient is a 45-year-old who presented with an almond-sized right axillary lump. Mammogram showed clustered pleomorphic calcifications associated with increased density in the right upper outer quadrant. Several large lymph nodes, some with pleomorphic calcifications, were also noted in the axilla and were consistent with metastasis. Ultrasound revealed two masses in the right breast at 9:30 and 10:00 measuring 2 and 2.5 cm. Three solid masses in the axilla measured up to three cm in size. Incisional biopsy of the breast lesions revealed invasive, poorly differentiated ductal carcinoma. Subsequent mastectomy and axillary node dissection confirmed a three cm invasive ductal carcinomagrade 3 by the Modified Bloom Richardson system.

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Margins were free. Estrogen and progesterone receptors were negative, and Her2neu receptors were positive. Four of 14 axillary lymph nodes were involved, with one metastasis measuring greater than 2 cm, and another focus revealing microscopic extracapsular extension less than 2 mm from the nodal capsule. She was staged with CT scans of the chest, abdomen, and pelvis. The CT scans revealed four very small, right pulmonary nodules, none larger than 7 mm, of uncertain etiology: They could be neoplastic or inflammatory. They were too small to biopsy, and a bone scan was negative. A PET scan was not performed. The medical oncologist decided to treat her as having non-metastatic disease, assuming the final stage was T2N2aM0. The plan was for serial chest CT scans for follow up. She received chemotherapy consisting of Adriamycin, Cytoxan, Taxol, and Herceptin. Four-month follow-up chest CT revealed stability of the nodules, and the patient was referred to radiation oncology for treatment recommendations. At this point a PET/CT scan was ordered. The indications were twofold. If the lung nodules were positive, suggesting uncontrolled metastatic disease, prophylactic chestwall radiation would have been abandoned. With her extensive initial nodal involvement, we were also concerned about the possibility of extensive nodal involvement in the supraclavicular, internal mammary, or mediastinal regions. The PET/CT scan was performed in the treatment position in a mold to allow its use in treatment portal planning, should it have been positive in those expanded nodal areas. Fortunately, the PET/CT scan was negative in this case, and we proceeded with standard chest-wall and nodal irradiation as shown in Figure 1:

Fi gure 1

Case #2. An 83-year-old woman with severe COPD requiring 24-hour oxygen

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supplementation presented with a large mass replacing the left breast and involving the skin. She had ignored the lesion for some time, and initially chose not to seek medical attention. She eventually agreed to a biopsy that revealed infiltrating ductal carcinoma. She was not a surgical candidate due to the skin involvement as well as her other comorbidities. As the tumor was estrogen and progesterone receptor positive, she was started on Tamoxifen. A PET/CT scan performed for staging and radiation treatment planning revealed a heterogeneously positive left breast mass involving overlying dermal structures compatible with the patients malignancy. A 1-cm left axillary node was noted with low-grade FDG activity. It was felt to indicate early metastasis involvement of this lymph node. Clinically, supraclavicular adenopathy was noted, which was not seen on PET/CT. No definite evidence of distant metastasis was noted. Based on the exam and scan this patients stage was T4aN3M0. Palliative radiation to the breast and nodal regions was recommended to prevent further oozing, swelling, or bleeding of the mass. Radiation treatment planning incorporated the clinical and PET/CT scan findings. As noted in Figure 1, standard fields without the aid of scans may have missed the axillary node seen on PET/CT scan. Figure 2 demonstrates how the PET/CT scan findings help define the radiation fields. PET/CT was beneficial to this patient by improving the quality of her radiation treatment and allowing comprehensive staging with one test.

Fi gur e 2 .

Case #3. This patient is a 42-year-old with bilateral breast cancer. Her stage was

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T3N1M0 on the right and T4N2M0 on the left. A PET/CT scan was not included in her initial staging. She underwent bilateral mastectomy and chemotherapy and was referred for prophylactic bilateral chest wall radiation. Standard chest wall and supraclavicular fields were treated. At her 3-month follow-up visit, new nodules on her left chest at the posterior axillary line were noted. A PET/CT scan was obtained. The suspicious nodules were hypermetabolic, as was an AP window mediastinal lymph node (Figure 3).

Fi gur e 3 .

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On review of the prior radiation treatment plan, the new chest wall nodules appeared to have arisen at or near the lateral edge of the radiation field (Figure 4). Skin biopsy of a lesion confirmed recurrent breast cancer, and the patient was referred back to medical oncology for further chemotherapy. In retrospect, a PET/CT scan prior to initiation of radiation may have identified her recurrence early, and allowed for adequate coverage of the disease with customized radiation fields. It would have also identified early mediastinal node involvement.

Fi gur e 4 .

Conclusions. PET/CT scanning is a major new tool in the effort to successfully treat women with breast cancer. It provides more accurate staging of disease, which guides therapeutic decisions. For radiation oncologists, treatment planning PET/CT scans will diminish the rate of marginal misses in treatment of the breast, chest wall, and/or surrounding nodal regions. For our patients, it provides a more convenient and comprehensive staging tool. References
1. Jemal J, Tiwari RC, Murray T et al. Cancer Statistics, 2004. CA A Cancer Journal for Clinicians 2004:54,1:1-29. 2. Tse NY, Hoh CK, Hawkins RA et al. The application of positron emission tomographic imaging with flurodeoxyglucose to the evaluation of breast disease. Ann Surg 1992;216:27-34. 3. Wahl RI. Overview of the current status of PET in breast cancer imaging. J Nucl Med 1998;187:743-750. 4. Port ER, Young H, Gonen M etal. 18-F-2-deoxy-D-glucose positron emision tomography scanning affects surgical management in selected patients with high risk, operable breast cancer. Ann Surg Omcol 2006: 13(5):677-84. 5. Antoch G, Saoudi N, Kuehl H et al. Accuracy of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol 2004;22:4357-4368. 6. Eubank WB, Mankoff DA, Takasugi J et al. 18-fluorodeoxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer. J Clin Oncol 2001:19:3516-3523. 7. Crippa F, Seregni E, Agresti R et al. Association between 18 fluorodeoxyglucose uptake and postoperative histopathology, hormone receptor status, thymidine labeling index and p53 in primary breast cancer: a preliminary observation. Eur Nucl Med 1998:25:1429-1434.

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10. PET/CT in Gynecologic Radiation Therapy Abhijit Deshmukh, MD

Gynecologic cancers seen in radiation therapy practice include carcinomas of the cervix, uterus, vagina, and vulva. Radiation therapy plays an important role in the management of these cancers, either as definitive therapy or as adjuvant treatment after surgery. In addition, radiation therapy may have a role in ovarian cancer, although its use as part of the initial treatment strategy has fallen out of favor in comparison to chemotherapy. Gynecologic cancers are, in general, thought to begin as localized lesions that may spread in an orderly progressive fashion to lymphatics and distant sites. Accurate staging is therefore of critical importance in radiation treatment planning for gynecologic cancer. The more sensitive and specific the diagnostic information available to the radiation oncologist, the better chance all sites of disease can be encompassed and effectively treated. This chapter will present some cases seen in our practice in which PET/CT helped in staging, treatment planning, and follow-up. It is not intended as a comprehensive chapter but rather as an illustration of the benefit of using PET/CT in day-to-day radiation oncology practice. Cer vical Carcinoma. There were an estimated 10,520 cases of cervical cancer in the United States in 2004, and 3,900 deaths. Early-stage patients may be managed with either surgery or radiation therapy, while locally advanced patients are usually treated with concurrent chemoradiotherapy. Important prognostic factors include FIGO stage, tumor volume, and pelvic or para-aortic adenopathy. Inoue retrospectively analyzed 875 patients with resected IB to IIB disease and found survival rates of 89%, 81%, 63%, and 41% in patients with no nodes, one node, 2 to 3 nodes, and 4 to 18 nodes positive, respectively.1 The location of involved nodes (obturator, external iliac, common iliac, or para-aortic) also has prognostic importance, as reported by Terada.2 Indeed, the GOG reported that para-aortic adenopathy was the most significant prognostic factor among patients treated with radiation therapy.3 Staging of cervical cancer according to FIGO rules is based upon exam under anesthesia as well as allowed procedures including colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, IVP, chest X-ray, and bone scan. Additional tests that may be used to determine the treatment plan, but do not change the stage, include lymphangiography, MRI, CT, PET, arteriography, laparoscopy, and laparotomy. PET has been compared to conventional CT and MRI staging, particularly in evaluation of lymph nodes. Grigsby reported on 101 consecutive patients who underwent both PET and CT prior to standard radiation with chemotherapy if indicated.4 CT demonstrated abnormally enlarged pelvic nodes in 20% and para-aortic nodes in 7% of patients. PET demonstrated abnormal FDG uptake in pelvic nodes in 67%, para-aortic nodes in 21%, and supraclavicular nodes in 8%. Two-year progression-free survival

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based on para-aortic node status, was 64% in patients with negative CT and PET, but only 18% with negative CT and positive PET. Patients with both CT and PET positive had a 14% PFS. PET has also been shown to be superior to MRI in nodal evaluation. Reinhardt et al. reported on 35 patients with stages IB or II cervix cancer who underwent radical hysterectomy and pelvic lymphadenectomy. PET had higher sensitivity and specificity than MRI, 91% versus 73% and 100% versus 83% respectively. Case #1. S.M., a 32-year-old female, presented with irregular vaginal bleeding and lower abdominal pain. Cervical biopsies confirmed squamous cell carcinoma. Exam showed stage T1b1 disease. Chest X-ray and CT of the abdomen and pelvis showed no evidence of metastasis. However, whole-body PET revealed a focus of activity in a small right paraspinous node at L5 as well as a small focus in the left pelvis (Figure 1). Direct extension posteriorly and laterally in the pelvis was also seen on PET.

Fi gure 1 .

She underwent exploratory laparotomy and excision of a right para-aortic lymph node, which was positive for metastatic disease on frozen section. Excision of a left paraaortic node also confirmed metastatic carcinoma. Her treatment plan involved delivery of 41 Gy to the upper para-aortic nodes, 46 Gy to the lower para-aortic nodes, and 50 Gy to the pelvis, with concurrent cisplatin chemotherapy, followed by HDR intracavitary brachytherapy to deliver an additional 30 Gy to point A in five sessions.

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Case #2. S.C., a 41-year-old female, presented with a 4-month history of irregular vaginal bleeding and pelvic pain. Pap smear was suspicious for carcinoma. Exam revealed an 8-cm exophytic, fungating mass replacing the cervix, with extension and fixation to the left pelvic sidewall. Cervical biopsy confirmed invasive, poorly differentiated squamous cell carcinoma. She was clinically staged IIIB. CT of the abdomen and pelvis showed left hydronephrosis and hydroureter as well as an 8.1 x 6.2 cm cervical mass, but no definite lymphadenopathy. However, PET showed two FDG-avid, non-enlarged (<1.5 cm) nodes in the left internal iliac and right pelvic wall/obturator regions (Figures 2 and 3).

Fi gure 2 .

Fi gure 3 .

She received 45 Gy to the pelvis with IMRT boost to bilateral pelvic sidewalls to 54 to 55 Gy with concurrent cisplatin chemotherapy. Follow-up PET/CT then showed decreased FDG uptake in the cervical mass from initial SUV of 21.0 down to 10.9, in the left iliac node from 5.0 to 2.1, and resolution of uptake in the right obturator node from initial SUV of 11.0. She then received 30 Gy in five fractions to point A using HDR tandem and ring brachytherapy. Subsequent PET/CT two months post-brachytherapy showed further decline in FDG uptake in the cervical mass from SUV of 10.9 to 5.2. No FDG-avid pelvic or abdominal nodes were seen.

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Vaginal Cancer. There were an estimated 2,160 cases of vaginal cancer in the United States in 2004, and 790 deaths due to this disease. Vaginal cancer involving the upper third of the vagina can spread to parametria and have lymphatic drainage similar to cervical cancer. Lesions of the lower vagina can spread to the urogenital diaphragm, levator ani muscles, and pelvic fascia. Lymphatic drainage occurs via the inguinal, femoral, and external iliac nodes. Prognostic factors include stage of disease, which is based on local invasion of tumor into parametrium or pelvic sidewall, and lymphatic or distant metastases. FIGO stage is determined on the basis of exam under anesthesia, colposcopy (and Schiller test), chest X-ray, IVP, barium enema, cystoscopy, and proctoscopy. CT and MRI are also routinely used in evaluation. Search of the literature did not reveal published experience with PET in staging vaginal cancer, but it was strongly recommended as part of the standard evaluation for vaginal cancers, based on similarities with cervical cancer.5 The majority of patients with vaginal cancer are treated primarily with radiation therapy, with the addition of concurrent cisplatin-based chemotherapy in locally advanced cases. Case #3. H.W., a 67-year-old female, presented with a right groin mass, biopsy of which showed metastatic squamous cell carcinoma. Staging work-up included negative CT of the chest, abdomen, and pelvis; bone scan; and colonoscopy. On evaluation by a gynecologic oncologist, she was noted to have a 1.5 x 1.5-cm raised, slightly erythematous lesion just inside the anterior right introitus. Biopsy of this lesion confirmed poorly differentiated, non-keratinizing squamous cell carcinoma, involving submucosal tissues only. Subsequent PET scan showed a single, small, FDG-positive node in the mid-abdominal pre-aortic region (Figure 4).

Fi gur e 4 .

She received 45 Gy to the pelvis and inguinal and para-aortic nodes, followed by 5.4 Gy boost to the primary tumor in the distal vagina. She then received 18 Gy HDR intracavitary boost via vaginal cylinder. Interestingly, PET one month after brachytherapy showed the para-aortic node to be larger and more metabolically active, with SUV increased from 4.3 to 6.0 (Figure 5).

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F igur e 5 . Follow-up PET at 4 months was essentially stable (SUV 6.2 versus 6.0 previously). However, by 7 months post-treatment, the hypermetabolic node had resolved (Figure 6).

F igu re 6. Unfortunately, 4 months after her negative PET, the same node was found to be hypermetabolic in comparison with liver activity and was considered to be suspicious (Figure 7).

F igu re 7. Short-term follow-up PET is pending.

Bibliography
1. Inoue T, Morita K: The prognostic significance of number of positive nodes in cervical carcinoma stages IB, IIA, and IIB. Cancer. 1990;65:1923. 2. Terada KY, Morley GW, Roberts JA: Stage IB carcinoma of the cervix with lymph node metastases. Gynecol Oncol. 1988;31:389. 3. Stehman FB, Bundy BN, DiSaia PJ, et al: Carcinoma of the cervix treated with radiation therapy: I. A multivariate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer. 1991;67:2776. 4. Grigsby PW, Siegel BA, Dehdashti F: Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol. 2001; 19(17): 3745. 5. Grigsby PW: Vaginal cancer. Current treatment options in oncology. Curr Treat Options Oncol. 2002; 3:125.

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11. L ym phoma s Ti m o th y J a m ie s on , MD , B ru ce Tr i pp , M D
Introduction. In the United States, lymphomaincluding Hodgkins disease (HD) and Non-Hodgkins Lymphoma (NHL)is diagnosed in over 60,000 persons annually, and kills over 20,000. The incidence of NHL has increased steadily in the past 25 years. The cure rate for HD has improved from 71% to 84% in the past 3 decades, and from 47% to 56% for NHL.1 The increase in cure rates has led to an effort to reduce treatment-related side effects. Thus, altered chemotherapy regimens and smaller radiation fields and doses have been implemented. Significant factors in further reduction of toxicity and improvement in survival will include better assessment of disease stage, localization, and response to treatment, enabling physicians to better tailor their treatment. PET/CT will likely play a large role in that effort. We will briefly review the utility of PET in lymphoma management. Initial Staging. Staging of lymphoma requires a history and physical, laboratory data, bone marrow biopsy, and radiographic studies. PET has been shown in numerous studies to be more accurate than CT in defining sites of disease.2,3 Stumpe demonstrated a PET sensitivity of 89% and specificity of 100% in NHL, and 86% and 96%, respectively, for HD. In contrast, CT scans had a sensitivity of 86% and specificity of 67% for NHL, and 81% and 41%, respectively, for HD.4 Low-grade lymphomas had been detected with lower sensitivity in older PET scanners, but new generation highresolution equipment has overcome this limitation.2 PET has been shown to change the staging in 8% to 16% of NHL patients. 3% Up to 41% of HD patients were upstaged in a recent study, as PET detected splenic and other extra nodal site involvement in about 20% of cases where CT was considered negative.5 A dedicated dual modality PET/CT has been shown to be more accurate in initial staging (84%) than side-by-side PET and CT (76%), or either modality alone (PET - 64%, CT - 63%) in a study of 260 patients with solid tumors based upon histopathology and clinical follow up.6 Determinations of lymphomatous involvement by CT are obviously based upon nodal size or anatomic data alone, and the complementary functional information from PET results in superior accuracy in defining sites of disease. CT will continue to be important in treatment planning as it has better anatomic resolution than the corresponding PET. Response to Treatment. PET is an excellent prognostic indicator at the completion of first-line chemotherapy. The utility of CT scans alone in this setting is complicated by the conundrum of residual masses that may be fibrosis or active tumor. PET can better determine the viability of these masses. Spaepen performed PET before and after firstline chemotherapy in 93 patients with early stage NHL.7 Sixty-seven patients had a negative post-chemotherapy scan, and only 11 relapsed (median progression-free

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survival 14 months), whereas all 26 patients with positive PET scans relapsed (median progression-free survival 2 months). Fourteen of these 26 patients had negative CT scans after first-line chemotherapy, and thus would have been incorrectly labeled as complete responders if a PET had not been performed. Lavely reported that 21 NHL patients had negative PET scans after chemotherapy alone.8 Five relapsed in the site of initial disease. Twelve patients treated with combined modality had negative PET scans after chemotherapy, and none relapsed. The authors concluded that a negative PET scan thus does not preclude the presence of microscopic disease, and thus radiation therapy should still be considered after a complete radiographic response to chemotherapy in early-stage NHL. As small volume microscopic disease is not readily detected by PET, the initial sites of disease (ie, the pre-chemotherapy PET scan) should be carefully scrutinized in determining consolidative radiation fields. Several investigators have shown the utility of PET before completion of first-line chemotherapy in predicting outcome.3 This utility might allow oncologists to switch from ineffective chemotherapy to alternative second-line chemotherapy or more aggressive alternatives such as bone marrow transplant earlier in the patients treatment course; prospective studies will need to be performed to demonstrate the utility of this approach. As more drug combinations become available, the ability to predict response after only one or two cycles will be increasingly more important, so one can switch to a more effective regimen before excess toxicity is imparted and further time is wasted. Conclusions. PET/CT is an essential tool in the staging of lymphomas, its response to treatment, and in defining radiation fields. Its use in predicting response early during the first course of chemotherapy may ultimately improve outcomes in patients resistant to first-line chemotherapy. Though a negative PET scan after chemotherapy confers a better prognosis than a positive PET, consolidative radiation therapy should still be strongly considered in those with negative PET scans, as relapse in the site of initial disease in this setting is not uncommon. Bibliography.
1. Jemal, A., et al: Cancer Statistics, 2004. CA Cancer J Clin 54:8-29, 2004 2. Kumar, R., et al: Utility of fluorodeoxyglucose-PET imaging in the management of patients with Hodgkins and nonHodgkins lymphomas. Rad Clin N. Am 42:1083-1100, 2004. 3. Israel, O., et al: Positron Emission Tomography in the Evaluation of Lymphoma. Seminars in Nuclear Medicine 3:166-179, 2004 4. Stumpe, KDM, et al: Whole-body PET using fluorodeoxyglucose for staging lymphoma: Effectiveness and comparison with CT. Eur J Nucl Med 25:721-728, 1998. 5. Partridge, S., et al: PET in the pretreatment staging of Hodgkins disease: influence on patient management in a single institution. Ann Oncol 11:1273-1279, 2000. 6. Antoch, G., et al: Accuracy of whole-body dual-modality PET and CT for tumor staging in solid tumors: Comparision with CT and PET. J Clin Oncol 22:4357-4368, 2004. 7. Spaepen, K., et al: Prognostic value of PET after first-line chemotherapy in NHL: Is PET a valid alternative to conventional diagnostic methods? J Clin Oncol 19:414-419, 2001 8. Lavely, W., et al: FDG PET in the follow-up management of patients with newly diagnosed Hodgkin and NonHodgkin Lymphoma after first-line chemotherapy. Int. J Radiation Oncology Biol. Phys. 57:307-315, 2003.

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12. BRAIN TUMORS Mark Augspurger, MD

Introduction. The diagnosis of a primary or metastatic neoplasm within the central nervous system (CNS) can present therapeutic challenges. Surgery may be necessary to establish a diagnosis and/or alleviate acute mass effects. Due to the importance of adjacent functional brain tissue, surgery, at best, is a debulking procedure even with a gross total resection due to inability to get negative margins. With rare exception, chemotherapy effectiveness is limited by lack of tumor sensitivity and poor diffusion across the blood-brain barrier. Radiation therapy is not as constrained by these limitations, and therefore has become entrenched as an essential treatment modality in the management of both primary and metastatic brain neoplasms. The scope of the brain tumor problem is substantial. The frequency of primary CNS malignancies is directly associated with patient age with a total annual incidence of 18,000 cases per year in the United States. Of these patients, 13,000 will die annually1. Additionally, over 100,000 patients will have metastatic tumors spread to the brain each year2. Primary brain tumors can arise from a variety of tissues. The most common primary brain tumors in adults are of glial origin. Unfortunately, over 50% of these adult glial tumors will be malignant (anaplastic glioma or glioblastoma multiforme). As these glial tumors comprise the bulk of the primary CNS tumors the radiation oncologist will encounter, the remainder of this chapter will refer to this subset of tumors when discussing primary brain tumors. While radiation therapy has been proven effective, it is not without limitations. The primary obstacles in radiation delivery are normal tissue tolerance and tumor volume identification. Both issues complicate radiation treatment planning, and planning could be improved greatly if the physician could better differentiate between the target and normal tissue. Brain Tumor Imaging. CT has been widely available to the radiation oncologist since the 1970s. This imaging provided the first in-vivo imaging of the neuroanatomy2. The Houndsfield units of the CT image are directly related to the density of tissue, and ionic contrast agents help detect the increased vascularity often seen with high-grade gliomas. Although the images are coarse, CT continues to play a role in both diagnosis and treatment planning for the radiation oncologist, due to its swift acquisition times and minimal spatial distortion. Within the CNS, MRI has largely replaced CT for diagnostic purposes. Compared to CT, T1 weighted MRI images provide a superior representation of the brain parenchyma, and T2 weighted images can be obtained to identify extent of the cerebral edema. Also, breakdown of the blood-brain barrier can be identified by gadolinium contrast

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enhancement. In addition, this modality can directly obtain images in the sagital, axial, or coronal planes. Taken together, these properties make MRI an ideal anatomical imaging technique. Functional imaging of the brain with Positron Emission Tomography (PET) has also proven to be useful in the evaluation of brain tumors. This capability has been present since the 1980s2. At that time, however, PET imaging was primarily limited to academic institutions and was considered mainly a research tool. Today, the widespread availability of PET scanning, has allowed the oncologist to use this modality in the clinical arena. Perhaps one of the most important recent technological advances for the radiation oncologist has been the ability to fuse images from various diagnostic techniques3. MRI images are optimal for imaging brain tumor anatomy. When now fused to the images of a PET/CT, the radiation oncologist now has an unprecedented way to visualize the tumor in relation to the normal tissue and surrounding bony landmarks. As a result, target volumes can be designated not only by breakdown of the blood brain-barrier and edema, but also by metabolic tumor activity (Figure 1). PET Imaging of Brain Tumors. Generally, higher metabolic activity correlates with increased uptake of the FDG. This is true in both tumors and normal tissue. Also, metabolic activity is closely associated with the histologic grade of the tumor. As the prognosis of a patient with a glial brain tumor is highly dependent upon (and inversely proportional to) the grade of the tumor, by inference the PET image intensity provides prognostic information to the oncologist.4,5 Although tumor grade also correlates with the level of contrast enhancement seen on MRI, the FDG uptake on a PET scan has been shown to be a more accurate predictor.2 Normal brain parenchyma has a significant glucose metabolism that unfortunately results in a high degree of background uptake of FDG. This characteristic negatively impacts the ability of PET/CT to detect lesions of intermediate grade. The background FDG uptake of white and gray brain matter can, however, serve as a useful reference when evaluating primary brain tumors2. Due to their high rate of proliferation and glycolysis, the malignant gliomas exhibit significant FDG uptake on PET imaging2. These tumors will have uptake similar to or greater than the adjacent brain gray matter. Conversely, low-grade glial neoplasms usually have relatively lower levels of glycolysis, and appear to have FDG uptake more similar to brain white matter. Of course, many brain tumors may contain various histologic grades that may not be readily apparent on CT or MRI. PET/CT, however, can often discern differential uptake across a tumor. Indeed, at some institutions, PET imaging with MR fusion has been incorporated into software for stereotactic biopsy guidance in an effort to reduce the risk for sampling error, and biopsy the most aggressive portion of the suspected tumor6.

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To date, routine brain screening with PET/CT has been disappointing. Although many metastatic brain tumors can be identified on PET/CT imaging, the intense background uptake of normal brain coupled with minimal tumor burden and the frequent location of metastasis at the gray-white junction, limits the usefulness of PET as a screening study in asymptomatic patients. In our experience, PET/CT is most useful in evaluating brain metastasis in symptomatic patients or in patients who have inconclusive readings on their MRI studies. Treatment Planning for the Radiation Oncologist with PET/CT and MR Fusion. The Simulation. Patients are simulated and treated in the supine position. The patients head is placed in a neutral or flexed position, and at least four fiducial markers are placed on the patients skin. Immobilization consists of an Aquaplastic mask extending from the vertex of the scalp to the shoulders and is attached to a MED-TEC S-type headboard. The mask is removed and IV access is obtained. FDG is administered as in previous chapters. The patient is made comfortable in a solitary, sensory-deprived room to minimize brain activity and resultant glucose metabolism. After 45 minutes, a PET/CT is then performed. Laser markings and couch position are recorded in the PET/CT suite for patient set-up and shifts. The patient is then taken to the MRI department and set up in a similar fashion. As the patient will not fit in the MRI brain coil in this position, the full-body coil is used. T1with contrast and T2 axial images are obtained at the same 3 mm spacing as the CT. The PET/CT is then fused to the MR data set in the dosimetry department. Generally, the MRI to PET/CT fusion is within 2 mm concordance. The Plan. For a malignant glioma, we will treat the edema plus a 2 cm margin to 4500 cGy. A boost will then be designed to treat the tumor plus 2.5-cm margin to a dose greater than 6000 cGy (RTOG parameters). In contouring the initial volume, the T2 MRI data set is primarily used as edema is well visualized. The PET/CT uptake is generally well covered within this volume. If uptake is seen on the PET/CT extending beyond the edema, this is also given a 2-cm margin. The boost PTV (planning target volume) is designed utilizing the T1 contrast-enhanced data set as well as the PET/CT study. All monitored unit calculations are done on the CT data set. Radiosurger y. PET/CT images can also be used to assist in the planning of radiosurgical procedures. In this setting, the MRI data set obtained for radiosurgical planning is fused to the PET/CT images. Reports in the literature indicate that when PET/CT has been incorporated, changes will be made to the MRI-based target volume in approximately 70% of cases7. PET imaging has also been helpful in assessing the tumor response to radiosurgery8. In our experience, PET/CT has been most beneficial in the radiosurgical planning of patients with recurrent gliomas. Figure 1 shows a PET/CT image of a patient who underwent gamma knife radiosurgery at our facilty.

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Fi gure 1 . The patient had previously had one radiosurgical procedure and the PET/CT was used to help differentiate the volume of active tumor progression from the previous treatment changes.

Evaluation of Response and Follow-Up. PET imaging can be an important tool in the evaluation and management of patients after they have completed a definitive course of treatment. It is usually quite difficult to differentiate recurrent neoplasm from surgical and radiation changes that occur within the brain parenchyma after treatment on MR or CT imaging. Surgical changes alone do not increase glycolitic metabolism and therefore do not show increased FDG uptake on PET imaging2. Similarly, necrosis can occur following radiation therapy and typically shows little uptake on PET imaging9. Overall, when PET is used to distinguish between necrosis and recurrent tumor, studies have shown a sensitivity of 75% and specificity of 80%2. Unfortunately this is complicated by the fact that many patients have both tumor and necrosis present at the time of progression. Nevertheless, at our institution we utilize both PET/CT and MRI for follow-up of our patients with high-risk glial tumors. The following case illustrates the benefit of this approach.

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Case Study. DG is a 51-year-old male who was found to have GBM of the right temporal lobe in 2000. He underwent a gross total resection followed by adjuvant radiation through an IMRT approach. He also received concurrent Temozolamide. On follow up MRI in January 2004, he was found to have two small (less than 5mm) nodules (Figure 2) adjacent to the surgical cavity. Repeat MRI in March 2004 showed no change. A PET/CT was then performed that showed no uptake in the areas of concern on MRI. He was, however, noted to have a 1 cm area of abnormal uptake in the right occipital lobe (Figure 3).

Fi gure 2 .

Fig ure 3.

Fi gure 4 .

Three weeks later, the patient presented to clinic with severe headache and nausea, and an emergent MRI was obtained. This study showed a 3-cm ring enhancing lesion in the occipital lobe with surrounding edema (Figure 4). Again, no new abnormalities were noted around the prior operative site. The patient underwent craniotomy the following day and was found to have a second glioblastoma
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in the occipital lobe. Future Applications. Due to the relatively high background FDG uptake of normal brain parenchyma, future PET imaging of brain tumors will likely be done with tracers other than FDG. Amino acid metabolism is higher in glial neoplasms than in normal brain tissue. For example, C11-methionine has been studied and reveals good contrast between tumor tissues and normal brain10,11. Other radiolabeled amino acids are being studied as well. Lipid metabolism with F18-fluorocholine may prove to be a useful tracer for brain tumor imaging11. Finally, O15 tracers have been used to study cerebral blood flow2. This could be potentially useful to locate areas of functional criticality prior to radiosurgery. Wherever these exciting paths may lead, it is clear that PET/CT imaging will continue to be an invaluable tool in the management of brain tumors. References.
1) Jemal J, Tiwari RC, Murray T et al. Cancer Statistics, 2004. CA A Cancer Journal for Clinicians 2004;v54,1:1-29. 2) Wong TZ, van der Westhuizen GJ, Coleman RE. Brain Tumors. In: Oehr P, Biersack HJ, Coleman RE (eds) PET and PET-CT in Oncology. Springer, Verlag Berlin Heidelberg New York, pp 113-125. 3) Wong TZ, Turkington TG, Hawk TC et al. PET and brain tumor image fusion. Cancer J 2004;10(4):234-42. 4) Pardo FS, Aronen HJ, Fitzek M et al. Correlation of FDG-PET interpretation with survival in a cohort of glioma patients. Anticancer Res 2004; 24(4):2359-65. 5) Padma MV, Said S, Jacobs M et al. Prediction of pathology and survival by FDG PET in gliomas. J Nuerooncol 2003; 64(3):227-37. 6) Yap JT, Carney JP, Hall NC et al. Image-guided cancer therapy using PET/CT. Cancer J 2004; 10(4)221-33. 7) Levivier M, Massager N, Wikler D et al. Use of stereotactic PET images in dosimetry planning of radiosurgery for brain tumors: clinical experience and proposed classification. J Nuc Med 2004; 45(7):1146-54. 8) Lee JK, Liu RS, Shiang HR et al. Usefulness of semiquantitative FDG-PET in the prediction of brain tumor response to gamma knife radiosurgery. J Comput Assist Tomogr 2003; 27(4):525-9. 9) Hustinx R, Pourdehnad M, Kaschten B et al. PET imaging for differentiating recurrent brain tumor from radiation necrosis. Radiol Clin North Am 2005; 43(1):35-47. 10) Kracht LW, Milectic H, Busch S et al. Delineation of brain tumor extent with [11C]L-methionine positron emission tomography: local comparison with stereotactic histopathology. Clin Cancer Res 2004; 10(21):7163-70. 11) Becherer A, Karanikas G Szabo M et al. Brain tumor imaging with PET: a comparison between [18F] fluorodopa and [11C]methionine. Eur J Nucl Med Mol Imaging 2003; 30(11):1561-7.

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13. PET/CT IN RADIATION TREATMENT PLANNING FOR COLORECTAL CANCER Dwelvin Simmons, MD
Colorectal cancer is the third most common malignancy in the United States1. In 2004 there were approximately 140,000 new cases and of these, 40,000 were rectal tumors. The incidence of colon cancer is equal in males versus females and is slightly higher for males in the rectum. The majority of these cases are adenocarcinomas histologically2. The primary treatment of colorectal cancer is surgical resection. Cure rates are excellent in patients with early-staged tumors. For more advanced tumors, there is a major risk for local and systemic failure. Chemotherapy and radiation in the (neo) adjuvant setting has unquestionably improved local failure and distant metastatic rates, ultimately impacting survival3. There continues to be debate over whether chemoradiation should be given in the neoadjuvant or adjuvant setting. Preoperatively, it may downstage the tumor, making it more surgically approachable, perhaps converting some patients to candidates for sphincter sparing procedures. Postoperatively, the role is to extirpate residual disease at the primary site, and nodal basins. When indicated, the survival advantages provided by chemotherapy and radiation are clear in rectal cancer.4,5,6 The clinical stage of colorectal cancer clearly impacts prognosis. Accurate staging of this disease can ensure that the most appropriate treatment be given. Along with colonoscopy and biopsy, the radiographic evaluation of colorectal tumors is crucial. CT scans are useful for assessing invasion of neighboring structures as well as detection of distant metastasis. Endorectal ultrasounds as well as endorectal MRI are very accurate in assessing depth of tumor invasion7. FDG PET/CT is Medicare-approved for initial staging and follow-up of patients with colorectal malignancies. In comparison to CT alone, PET/CT is more sensitive and accurate for detection of tumor sites, especially with regard to regional lymph nodes8. It is unusual for colorectal cancer to produce nodes larger than 1 cm, making it difficult to assess metastatic disease from reactive lymph nodes. Endorectal ultrasound and endorectal MRI also predict regional lymph nodes poorly9. The design of conventional external beam treatment portals relies heavily upon the detection of the extent of disease. This has involved the use of contrast-enhanced CT simulation for 3D treatment planning. The field is designed to cover the primary site, presacral space, internal iliac, and distal common iliac nodes. Inguinal nodal coverage is necessary when tumor is within 2 cm of the anal verge. Fields typically include the perineum in postoperative cases. Typical preoperative radiation portals use a superior border at the L5 vertebral body and an inferior border 5 cm below palpable disease.

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Anterior and posterior portals include 1.5 cm of the pelvic brim. Lateral portals encompass the entire sacrum posteriorly and should have coverage of the internal iliac nodes. There should be an adequate anterior margin upon the rectum. If dosing beyond 45 Gy is necessary, these fields are appropriately reduced depending on the clinical situation. Some have even used smaller fields touting improved morbidity with similar results. IMRT has gained popularity given its ability to spare normal tissues and radiation induced toxicity. There is a wide array of techniques used to accomplish IMRT10. Ultimately, radiation given concurrently with chemotherapy in the preoperative or postoperative setting is only effective if the disease is appropriately targeted. Our practice advocates the use of PET/CT in the simulation process to help better define the target. Below are three cases in which the use of this imaging modality was crucial in defining treatment to all areas of disease: Case #1. A.B. is a 65-year-old man with a diagnosis of adenocarcinoma of the distal rectum with extension to the anal verge. The patient had experienced six months of tenesmus and bright red blood per rectum prior to colonoscopy. Biopsy returned the diagnosis. Of note, the remainder of the bowel had several polyps that were biopsied and found to be benign. An outside CT demonstrated rectal wall thickening at the primary site, but no evidence of metastasis or asynchronous primary. The patient was referred for preoperative radiation and chemotherapy prior to APR. He underwent PET/CT treatment planning with images shown (Figure 1).

Fi gure 1 .

This study demonstrated readily the primary site. No lymph node metastasis or hepatic metastasis was identified. However, there was an FDG avid cecal mass not seen at the time of colonoscopy, consistent with a synchronous primary. This patients treatment plan was changed to immediate right hemicolectomy and APR with postoperative therapy to follow.

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Case #2. C.L. is a patient with adenocarcinoma of the rectum (T3N1M0) with perianal skin involvement. This patient received an APR with seven of 21 nodes positive for disease. Margins were positive at the perianal skin. Preoperative CT scan demonstrated no positive lymph nodes and no hepatic metastasis. Intraoperatively, the liver was felt to be free of disease. The patient was referred for postoperative radiation and chemotherapy. He underwent PET/CT simulation for treatment planning with the images seen in Figure 2.

Fi gure 2 .

The residual disease at the primary site is impressive. The scan also demonstrated extensive disease at the pelvic sidewall and right common iliac node basin. Treatment portals were designed to encompass all of the disease appreciated in the pelvis.

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Case #3. L.M. is a 72-year-old patient with adenocarcinoma of the rectum 8 cm above the anal verge, diagnosed after two months of bright red blood per rectum and decreased stool caliber. The patient was referred for preoperative chemotherapy and radiation. Outside the CT showed no hepatic metastasis and no nodal involvement. The patient received PET/CT simulation for treatment planning. Her images are shown in Figure 3.

Fi gure 3 .

Note the node at the distal common iliac chain. This very easily could have been geographically missed using conventional radiation portals based upon conventional CT simulation. Fields were designed to adequately cover the disease with appropriate margin. Defining a target volume can vary to significant extent among observers, and any modality limiting this variance should be welcomed. It is becoming clear that good PET/CT imaging incorporated into the simulation process can improve radiation delivery. This has been demonstrated for lung tumors in which a study showed approximately 30% of patients had modification of their treatment portals due to PET imaging.11 Several studies have shown PET/CT to be extremely useful in the design of radiation portals for pelvic malignancies including rectal carcinomas and others.12,13 In conclusion, PET/CT is not infallible in its use for colorectal cancer. It is less specific than CT scans. PET/CT has difficulty distinguishing inflammatory nodal disease from active tumor. Mucinous tumors accumulate less FDG, thereby decreasing the sensitivity of PET/CT in this type of colorectal tumor. At present, this modality is not widely available, but this is rapidly changing. It is our practice to routinely use PET/CT as part of the simulation process for colorectal cancer. Data from PET and images is coregistered on an integrated PET/CT system, during one image acquisition session, limiting image fusion deviations. Our practice uses the CMS focal fusion software and a treatment plan is then derived using XIO, CMSs treatment planning system. Currently we are evaluating the fusion of PET/CT with MRI and its role in the treatment planning of colorectal cancer.

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Bibliography:
1) Jemal, A., et al: Cancer Statistics, 2004. Cancer J Clin 54:8-29, 2004. 2) Heriot A et al: Preoperative staging of rectal carcinoma. Br J Surg. 1998; 86: 17-28. 3) Krook J.E. et al: Effective surgical adjuvant therapy for high risk rectal carcinoma. N Engl J Med 1991; 324 (II): 709-15. 4) Marsh, R et al: Preoperative Treatment of Patients with Locally Advanced Unresectable rectal adenocarcinoma utilizing continuous 5FU and Radiation. Cancer Vol 78; 2 p 217-225. 5) Mendenhall W.M. et al: Does preoperative radiation enhance the probability of local control and survival in highrisk distal rectal cancer? Ann Surg 215: 696-705 1992. 6) Wong C.S et al: Local excision and post operative radiation therapy for rectal carcinoma. Int J. Radiat Oncol Biol Phys 25: 669-675, 1993. 7) Fleshman J W et al: Accuracy of TRUS in predicting stage of rectal cancer. Dis Colon Rectum 1992; 35: 823-929. 8) Abel-Nabi et al: Staging of primary colorectal carcinomas with FDG whole body PET. Radiology 206; 755-760. 9) Myerson R: Colon and Rectum. Principles and Practice of Radiation Oncology pp 1607-1629. copyright 2004 Lippincott Williams & Wilkins. 10) Chao K et al: Pelvic and Para-aortic Nodal Target Delineation. Practical Essentials of Inentisty Modulated Radiation Therapy p. 303-307 copyright 2005 Lippincott Williams & Wilkins. 11) Calvo 7 et al: 18F-FDG PET staging and restaging in rectal cancer treated with preoperative chemoradiation. Int J. Radiation Oncol Biol V 58 No. 2 pp 528-535. 12) Kantorora I et al: Routine 18F-FDG PET preoperative staging of colorectal cancer: Comparison with conventional staging and its impact on treatment decision making. J of nuclear medicine Vol. 44 No. 11 p. 1784-1788. 13) Meta J et al Impact of 18F-FDG PET in managing patients with colorectal cancer: The referring physicians perspective. Journal of nuclear medicine Vol 42. No. 4 p 586-590.

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14. CO NC L US I O N Shyam Paryani, MD, John Wells, Jr, MD, MS, and Mitchell Terk, MD
PET/CT simulation is a standard procedure in our department. We feel that it will replace the CT Simulator as the standard unit in all therapy departments. PET/CT has utility in simulation and treatment planning of the following malignancies: L un g Can cer Hea d & Nec k Cancer Br ea st Can ce r Cer vical & Uterine Cancer Lymphomas Brain Tumors Co l o r ec t a l Ca n c er s

The list of malignancies suitable for PET/CT will only expand. We have developed a practical and useful method to cost-effectively utilize a Siemens Biograph PET/CT in a multi-clinic environment. By using centralized treatment planning and a network, we are able to provide this service for our patients. We are happy to share our experiences with you. You may contact us at: P E T / C T C e n t e r o f N o r t h F lo ri da 1895 Kingsley Avenue, Suite 600 Orange Park, FL 32073 904-276-2338 Larry Wilf, MD, Medical Director John Wells, Jr, MD, Clinical Director Shyam Paryani, MD, Managing Partner Faye Lazar, NMT, Technical Director

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Any of the protocol(s) presented herein are for informational purposes and are not meant to substitute for any clinicians judgment in how best to use any medical devices. It is the clinician who makes all diagnostic determinations based upon education, learning, and experience. Note: Original images always lose a certain amount of detail when reproduced. 2006 Printed in USA 06-18-PO-1362 10-2006