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

2nd Edition

Reprint

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

2nd Edition

Shyam Paryani, MD, MS, MHAJohn Wells, Jr, MD, MSLarry Wilf, MDDouglas Johnson, MDWalter Scott, MDAnand Kuruvilla, MDAbhijit Deshmukh, MDSonja Schoeppel, MDMitchell Terk, MDTim Jamieson, MDBruce Tripp, MDDwelvin Simmons, MDMark Augspurger, MD

Jen Chang, PhDFaye Lazar, CNMTDiane WolinskiNitesh ParyaniJason ParyaniMitchell Terk, MDApril Mendoza, MDMichael Sinopoli, MDCraig Collie, MDDavid Graham, MDAllison Grow, MD, PhDBrian Thorndyke, PhD

PET/CT and Cyclotron Center of North FloridaFlorida Radiation Oncology GroupIntegrated Community Oncology NetworkOnCURE Medical CorpJacksonville, Florida

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

2nd Edition

Chapters:

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2Shyam Paryani, MD, Nitesh Paryani, Jason Paryani

2. Basic Principles of PET Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5Larry Wilf, MD and Walter Scott, MD

3. PET/CT Simulation & Patient Setup Considerations . . . . . . . . . . . . . . . . . . . . . . .9Faye Lazar, CNMT

4. Physics & Treatment Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15Jen Chang, PhD

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

6. Integrating PET/CT into Fusion Based Treatment Planning Process . . . . . . . . .33John Wells, Jr, MD, Allison Grow, MD, PhD, Brian Thorndyke, PhD

7. Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36Anand Kuruvilla, MD, Craig Collie, MD, David Graham, MD

8. Head & Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47April Mendoza, MD & Mike Sinopoli, MD

9. Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49Sonja Schoeppel, MD

10. GYN Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55Abhijit Deshmukh, MD

11. Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60Tim Jamieson, MD & Bruce Tripp, MD

12. Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62Mark Augspurger, MD

13. Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68Dwelvin Simmons, MD

14. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73Shyam Paryani, MD, John Wells, Jr, MD, Mitchell Terk, MD

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1. IntroductionShyam Paryani, Nitesh Paryani, Jason Paryani

The Florida Radiation Oncology Group (FROG) owns or operates thirteen Cancercenters in Northern Florida and Southern Georgia. The group originally startedpracticing in 1957. There are 19 physicians in the group including 2 dedicated Nuclearmedicine specialists. We obtained our first Positron Emission Tomography (PET)scanner in 2001 and have a dedicated GE Minitrace Cyclotron.

We implemented the world’s FIRST dedicated mobile PET/Computed Tomography (CT)simulator in 2004. The PET·CT unit houses a Siemens Biograph unit (Figure 1). Wehave since added another mobile Siemens Biograph unit in 2005.

It is vitally important that CTs and PETs be performed in the same anatomic positionand co-registered to allow for accurate treatment planning. We have dedicated PET andCT technologists as well as Radiation Therapists that simulate our patients. ThePET/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).

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We have developed a Network Model for our PET/CT and Treatment Planning Centerusing the CMS system. The PET/CT travels to each of our centers. All routinesimulations are performed on the unit. The data is then transferred to each center’sFocal Sim Unit. We are able to fuse PET and CTs, CTs with magnetic resonanceimaging (MRI), or CTs with previous CTs. The utility of PET along with CT will bediscussed in detail in subsequent chapters. The physician then contours the anatomyand outlines the appropriate tumor volumes (GTV, PTV). The data is thenelectronically transferred to our Centralized Dosimetry center which houses aBroadband Server and two XIO Treatment Planning Systems. Our dosimetry andphysics staff devise several alternative plans. These are then transmitted back to thecancer center where the physician can remotely review and compare multiple planson the Focal Sim. After a plan is selected, the physics team generates qualityassurance parameters and appropriate treatment parameters which are transmitted tothe appropriate linear accelerator.

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The network model has many advantages. Aside from economies of scale allowing usto share the PET/CT scanner with all of our facilities, there are many other cost savingsin our treatment planning area. Since all dosimetry functions are centralized, we areable to share personnel, standardize our planning and quality assurance, and decreasethe likelihood of errors.

For centers with multiple physical locations, we believe that this network is a practicalapproach which allows us to utilize PET/CT in treatment planning. We will describe ourexperience with PET/CT in radiation oncology and provide clinical examples on theutility of this modality. We feel strongly that PET/CT is an integral component of anymodern radiation oncology department.

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2. Basic Principles of PET Imaging: An OverviewLarry Wilf, MD, and Walter P. Scott, MD

Until recently, delineating target volumes for the diagnosis, staging, restaging, andtreatment of cancer has depended upon anatomic imaging. Computed tomography (CT)and MRI have been the mainstays in this function, as they both provide excellentanatomic detail. Unfortunately, what MRI and CT lack is a measurement of cellmetabolism. Historically in our patient practices, we have monitored treatment progressbased exclusively upon the change in size and appearance of tumor masses. Thissurveillance/measurement technique has proven less than optimal, as we have oftenbeen 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 cannotdifferentiate malignant from benign.

In the last few years, molecular imaging with F-18 deoxyglucose (FDG)-based PET hasaltered our imaging schemes with respect to oncologic imaging. What PET (molecularimaging) provides-that anatomic imaging does not–is a way to better differentiatebenign from malignant lesions as well as follow the changes that occur over time. PETyields a functional image–it tells us what the cells/lesions are doing. Oncologicmolecular imaging with FDG-PET is based on the fact that cancer cells often useglucose at a much higher rate than normal cells. PET scanning visualizes this uptakebecause FDG is an analogue of glucose and is similarly accumulated in metabolicallyactive cells. The increased use of glucose by tumor cells is due to 1) increased rates ofthe hexose monophosphate shunt, 2) increased hexokinase activity, and 3) increasedactivity of cell membrane glucose transportation. Metabolic activity is thus positivelycorrelated to FDG accumulation, and when the positron emitted by F-18 annihilateswith a nearby electron, two 511Kvp photons are emitted in opposite directions. Ringdetectors 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 aresolution of about 4 mm.

Because of its unique ability, molecular imaging has proved more sensitive and specificthan either CT or MRI for diagnosing, staging, and restaging cancer. In fact, a study byGambir and coworkers has recently summarized data in more than 26,000 patients andshown that PET was 10 to 20 % more accurate than conventional imaging.1

The major impetus, however, for recent PET expansion into clinical practice has beenthe ultimate acknowledgment by Medicare and insurance companies that PET not onlyprovides useful new information that the other imaging modalities cannot, but issignificantly less expensive than the surgical diagnostic alternatives. PET has thus beenshown to be very cost-effective from a patient management perspective.

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The major problem with PET imaging alone is the lack of correlative anatomy. Thecommon questions asked of the PET-interpreting radiologist by the referring physicianinclude: “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 limitedin resolution, so the ability to align/fuse its images to a more resolved image wouldseem beneficial. Researchers set out to resolve this problem by linking PET and CTimages together, aligned anatomically. This was first accomplished by software systemsthat would combine the two sets of images from two separate scanners. This processworked reasonably well but was limited by precision, patient positioning, themanipulation 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 sensitivityand 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 collaborationwith CTI (Knoxville, TN) and Siemens Medical Solutions (Hoffman Estates, IL)developed a dual-modality scanner combining both PET and CT in one unit. This unionenabled fusion/overlay to take place more easily as the patient could be scanned byboth modalities without moving (only the table moves) between scanners and at thesame sitting (not going to two departments, or two locations to accomplish).Furthermore, using CT data instead of transmission scanning data for attenuationcorrection (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 forstaging of cancer. From a therapy standpoint, a staging scan (depending upon thetumor type) can help determine who needs radiation therapy alone, chemotherapyalone, or both. Also, if the patient is to receive radiation therapy, the scan can beincorporated into the radiation therapy planning process, particularly useful for patientswho are to receive IMRT.

Another great benefit from molecular imaging with PET is the ability to determineresponsiveness of a tumor or metastasis to the radiation and/or chemotherapytreatment course. PET pharmaceutical uptake/activity/metabolism can be quantified andreferenced to a particular patient via Standard Uptake Value (SUV) units. This uniqueability allows one to empirically determine the therapeutic response of a giventreatment: In other words, “is it working, and how much?” With PET/CT this questioncan now be asked and answered often before significant anatomic imaging changes areeven detected by routine radiographic testing. The major medical frontier of rapid earlyresponse detection can now be crossed. We no longer need to rely solely upon a sizechange to determine tumor response (Figures 1 and 2). All cancer therapies have sideeffects that are uncomfortable to the patient and have substantial financial cost. Inparticular, new chemotherapeutic regimens are extremely expensive and somequestionably effective. Metabolic imaging serves a valuable role in the continuedevaluation of a particular therapy or treatment program. PET now has a very importantrole in maximizing the use of effective therapies, and minimizing the use of ineffective

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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 shownitself to be an important contributor to the field of Radiation Oncology. Prior tomolecular imaging, radiation therapy fields were determined by a CT scan alone thatcould delineate pathologic masses, but could not accurately determine the amount andextent of smaller tumor deposits. In 2002, a study by Dorendorf concluded thatcombined PET/CT changed the radiation treatment strategy from curative to palliative10% of the time. Furthermore, the radiation dose was changed (due to the PET/CTfindings) 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 anecessary component of our armamentarium. Having utilized PET/CT imaging routinelyfor over four years in our practice, no physician in our group would feel comfortablestaging, 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.

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Figure 1: Top image: PET/CT scan shows right inguinal non-enlarged lymph node now FDG positive, biopsyproven recurrent lymphoma. Bottom: older, negative PET/CT.

Figure 2: Corresponding CT images to Figure 1

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

The primary objective in managing cancer with radiation therapy is to deposit enoughdose to the malignancy to result in cancer cell death while minimizing the effect onsurrounding normal tissue. The treatment planning scan/setup must be performed ina reproducible, accurate, and precise manner to allow optimal definition of the area tobe treated.

Radiation therapy relies upon medical imaging throughout the treatment process,including the diagnosis, planning, treatment execution, and outcome evaluation fortreated patients. Recent advances in instrumentation, as well as advances in computerhardware and software in therapy and medical imaging, have enabled the radiationoncology team to use these tools in a precise three-dimensional format to designcustomized dose delivery patterns. The ultimate success of radiation therapy is directlyrelated to the effectiveness of the initial treatment planning procedure, and as treatmentvolumes are tighter and more customized, the importance of daily patient setup andpositioning is even more critical.

SSiimmuullaattiioonn aanndd PPoossiittiioonniinngg EEqquuiippmmeenntt.. CT has been routinely used for treatmentplanning for several years. CT detects grossly abnormal anatomy that can be identifiedfor targeting, and the density information it provides serves as the basis for patientdose calculation algorithms.

PET, as a complementary imaging modality, has recently proven useful in therapyplanning and disease monitoring in light of its enhanced ability to discriminate betweennormal and malignant tissues.

The new combined PET/CT scanners provide optimal information for radiation therapyplanning. PET and CT data sets are acquired with the patient lying in the same positionin one scanning session. The PET data and the CT data are imported into radiationtherapy planning systems, allowing the radiation oncology team to have access to bothanatomical and functional images that may be accurately fused. The PET datasupplements the CT data in that it allows better definition of the target volume.

PPEETT//CCTT SSccaannnneerr––EEqquuiippmmeenntt CCoonnssiiddeerraattiioonnss.. Imaging equipment to be used forradiation therapy planning must be able to duplicate the geometrical, mechanical, andoptical features of a radiation treatment unit. The equipment must allow the PET/CTSimulation Technologist (Sim Tech) the ability to position the patient in a positionidentical 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 includedwhen purchasing a combined PET/CT scanner to allow the patient to be scanned in thetreatment position. This tabletop should be evaluated for sag or tilt limits before the

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purchase is made. The table should have the capability to properly align the patient forthe treatment–planning scan. The bore diameter of the PET/CT gantry should bemeasured–the larger, the better. Greater bore diameter allows more flexibility for the useof special patient positioning and immobilization devices during the scanning process.

PPEETT//CCTT SSiimmuullaattiioonn––PPaattiieenntt SSeettuupp CCoonnssiiddeerraattiioonnss.. External Laser System. Inaddition to the PET/CT scanner modifications noted above, it is necessary to purchasean external laser system. Laser systems are calibrated specifically to the PET/CTsystem to align the beams with the isocenter of the unit. Typically 3-4 sources are usedto project points of light coinciding with the isocenter. The laser points or lines providereferences to align the patient in all three planes-transverse, sagital, and coronal. Thiscritical addition allows the Sim Tech to insure that the references are duplicated on boththe planning scan and the treatment unit.

LLooccaalliizzaattiioonn MMaarrkkiinngg SSuupppplliieess.. Appropriate marking tools such as India ink fortattooing and radio-opaque BB’s should be kept in the PET/CT scan room. Somepatients are set up with marks before arriving, while others will actually be simulated inthe PET/CT scanning area.

PPhhyyssiicciiaann PPrreessccrriippttiioonn.. Just as a medication prescription is a communication toolbetween a physician and a pharmacist, the radiation therapy prescription acts as thecommunication tool between the radiation oncologist and the treatment planning anddelivery team. For patients undergoing a planning PET/CT, the prescription should notonly include dose parameters, but also relevant information required for patient setup forthe 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 significantsetup errors, useless PET scans, and delayed treatments.The sim tech should be present for the treatment-planning scan, as he or she is theperson that best understands the prescription directive written by the radiation oncologist.

PPaattiieenntt PPrreeppaarraattiioonn.. Patients should be prepared prior to their arrival for the PET/CTtreatment-planning scan. Exams should be scheduled based on the individual patient’sphysical condition, medications, dietary restrictions and contrast requirements.Immobilization devices should be made in advance, and simulation marks on thepatient should be complete before the patient arrives for his scan. The patient and hisfamily should be educated as to the importance of the scan by the physician andtherapy technologists in advance. Clear-cut instructions and patient expectations helpthe patient and his family better understand the process and express their questionsand concerns prior to arrival at the PET/CT unit.Instructions should include:

• Patient preparation for the injection of FDG used for PET imaging (short sleevesor 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. Afriend or family member should be available if needed, and staff members should besensitive to the patient’s needs and feelings.

EEdduuccaattiioonn//CCoommmmuunniiccaattiioonn.. Communication and education affect the level of staff andpatient cooperation. Good instructions and rapport ultimately affect accuracy induplication of the treatment position. The entire interdisciplinary team mustcommunicate from start to finish. PET/CT staff members should be familiar withterminology, anatomy, treatment planning, and implementation of the radiation therapytreatment. The imaging staff should spend time with the therapy staff in the radiationtherapy department. They should observe patient setup, planning, and treatmentprocedures. This will give the imaging staff visual as well as verbal cues needed toproperly position the patient using devices and markings specific to that patient.Effective communication leads to successful planning and treatment.

SSccaann aanndd SSeettuupp.. It is imperative that the treatment planning images be acquired in theexact, precise position that will be used in the treatment process. The success of thetreatment program is directly related to this simulation procedure.

The PET/CT simulation process varies for each patient depending upon his uniquecondition, as well as the type and extent of his disease. One of the weakest links intreatment planning is poor patient positioning. If the patient is not comfortable and doesnot remain still, fancy plans and immobilization devices are rendered ineffective.Spending time with the patient before the procedure, educating and answering hisquestions, assist him in maintaining a comfortable and reproducible position.

PPoossiittiioonniinngg LLaannddmmaarrkkss.. Reproducible patient position is achieved by using a stablesurface and landmarks visible on or near the surface of the patient. Initial treatmentplanning references are appropriately marked using fiducial (skin) marks andorthogonally directed lasers for triangulation. These marks coincide with the projectionof external lasers on the skin, and determine the initial and tentative isocenter. Tattoosshould be used cautiously, especially when the patient is obese, loses weight duringtreatment, or has a change in tumor size: These factors can cause the skin to shift inrelation to internal anatomy.

IImmmmoobbiilliizzaattiioonn DDeevviicceess.. A comfortable position is used whenever possible to scanand treat the patient. Less movement is likely when a patient can maintain his/herposition with minimal or no discomfort. Immobilization devices are often used to helpthe 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 structureto ensure that the patient does not move.

• Simple immobilization devices that restrict some movement, but usually requirepatient cooperation.

• Complex immobilization devices that are individualized immobilizers that restrictpatient movement and ensure reproductive positioning.

Positioning aids are widely available, easy to use, and are used for over a period oftime for multiple patients. Head holders are made of formed plastic or polyurethane andcome in a variety of heights and contours that allow the proper head and neckangulations and positioning to be achieved. A prone pillow may be used to support thepatient’s chin and elevate the face from the tabletop when the patient is positionedprone. This device may be angled to free the face and forehead from pressure. Foamneck wells, foam cushions, and pillows are used as well for patient comfort. Arm boardsare contoured to the shape of the arm and are used to allow the arm to restcomfortably above the patient’s head and they allow more flexibility in achieving greaterarm tilt and extension.

Simple immobilization devices are often used in addition to positioning aids. They providesome 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 inthickness can be used to bind the patient’s feet together: This helps limit hip motion.Other devices include a head frame and bite block system that help maintain chin positionand 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 patient’s shoulder out of lateral head and neck fieldsby having the patient grasp and pull on straps running the full length of the body andaround the soles of the feet. Simple immobilization devices are easy to use and cost-effective. Several patients can use the same devices over time.

Each complex immobilization device is individualized. With such devices, unusual patientpositions can be achieved. They can be made of many different products such asplaster, thermoplastics, or Styrofoam™. For PET/CT scanning, the mold should be madeof a material that does not cause image artifacts. Thermoplastics, made by heating andmolding a softened sheet around the body part to be immobilized, are often ideal. Otherdevices may be made with polyurethane foam produced by combining two chemicalreactants in a plastic bag under the body part of interest. The patient is positioned in thetreatment position atop this bag and an exothermic reaction takes place. The resultantfoam expands around the anatomic structure causing the bag to conform to the shape ofthe body part, and hardens in approximately fifteen minutes.

Regardless of the immobilization device used, it must be available in the PET/CT suitefor use in positioning the patient for his scan.

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UUssee ooff CCoonnttrraasstt MMeeddiiaa.. Contrast materials help define and isolate anatomicalstructures and diseased tissues imaged with CT scans. Contrast media visuallyenhance anatomic structures that would be normally more difficult to see. Commonlyused contrast media include barium sulfate (oral) and either ionic or nonionicintravenous contrast media. Of note, treatment-planning systems use tissue densitycalculations in determining dose deposition when the “inhomogeneity correction”module is activated. In this instance, it is imperative that contrast-enhanced images notbe acquired for treatment planning use. All treatment-planning images should beacquired on the PET/CT unit first, without contrast, and only then a second CT withcontrast be obtained for the clinician’s use.

Before administration of any contrast medium, the patient should be carefully screenedfor potential reactions or complications. Severe allergic reactions have occurred insome patients requiring emergency intervention. Also, barium sulfate should not beused with a suspected bowel perforation or obstruction. In some cases, gases such ascarbon dioxide, oxygen, and air are used–especially in the rectal area to better definethe rectal wall location. Foley catheters are also sometimes used. The catheter balloonis 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 andsimulation. The PET/CT acquisition should be acquired with appropriate slice thicknessand spacing. Immobilization devices, patient positioning aids, and the laser systemmust be used to align the patient correctly. Our institution requires that the radiationtherapy technologist be present for patient positioning for the PET/CT treatment-planning scan. The data input from PET and CT images affects accurate planningoutput. Reproducibility and accuracy determine effectiveness.

QQuuaalliittyy IImmpprroovveemmeenntt.. To achieve high standards of patient care, the program forPET/CT treatment planning should continuously be assessed. The goal is to ensurethat accurate precise image data is provided and that patients are treated in the highestprofessional 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 availableduring 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 arenecessary 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 pursuescientific advancement and should value the role of their profession in this rapidlyevolving field. They should be familiar with the multiple facets of imaging therapy andtherapy equipment, and how each part integrates with the other to facilitate the patient’scare.

SSuummmmaarryy.. The treatment planning process involves an entire oncologic team. The useof PET imaging in addition to CT imaging can optimize the patient’s treatment planning.At our institution we have found great benefit in incorporating PET scan data intoradiotherapy planning. The additional information helps reduce or expand the treatmentfield 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 normaltissue exposure more confidently, and to better define potential volumes for doseintensification.

The radiation therapy process requires all members of the imaging and therapy team tobe totally committed to producing accurate, reproducible plans and treatment. Thewords “reproducible,” “accurate,” “precise,” and “effective” are used throughout thischapter. All these words apply to every step of setup and simulation–from the time thedecision is made to purchase imaging equipment, to the successful completion of ascan to be submitted to the therapy department.

For Further Reading:Paulino A.C. FDG-PET in Radiotherapy Treatment Planning: Pandora’s Box. International Journal of RadiationOncology 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 TargetDetermination 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. Imagingfor 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 ofRadiation 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 ofRadiation 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 PlanningJen Chang, PhD

IInnttrroodduuccttiioonn.. The goal of PET/CT utilization in radiation treatment planning is toprovide better delineation of target volumes such that an optimal radiation dose can beapplied to the target via conformal radiation treatment. Images obtained directly fromthe PET scanner, however, do not provide all the necessary information for targetdelineation; rather, they merely provide information on the distribution of positronannihilation events at the time when the PET scan was performed. Without someunderstanding of the tracer metabolic pathway, and their respective kinetics, and thelimitation of PET technology, it will be difficult to take full advantage of this excitingtechnology for treatment planning. This chapter will attempt to address concepts oftransforming images of annihilation events within organs and tissues into data useful inthe radiation treatment planning process.

TThhee HHiissttoorryy ooff PPoossiittrroonn DDiissccoovveerryy aanndd IIttss FFiirrsstt MMeeddiiccaall AApppplliiccaattiioonn.. In 1928, ayoung physicist, Paul Dirac, derived a relativistic equation describing the electron. Thiswork led Dirac to predict the existence of the positron, the electron’s antiparticle, via hisfamous Dirac equation. A positron has the mass of an electron but carries a positivecharge. When this particle meets an electron, they form an intermediate particle namedpositronium. This intermediate particle is very unstable and within a very short time (10-7sec), it annihilates. Its entire combined mass disappears and turns into an energeticelectromagnetic wave: two 0.511MeV photons traveling away from the point of annihilationin roughly opposite directions. Carl Anderson later observed the physical existence of thismagic antiparticle in 1932, and Dirac’s prediction of the existence of positrons ultimatelyled 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. Sweetand Gordon L. Brownell at Massachusetts General Hospital (MGH) in 19511. Sweet,Brownell, and their physics group developed and built a simple apparatus using twoopposing sodium iodide (NaI(Tl)) detectors and coincidence detection circuitry to localizebrain tumors. In the same year, Wrenn, Good, and Handler independently described andpublished their studies of positron annihilation for localizing brain tumors.2

TThhee HHiissttoorryy ooff PPoossiittrroonn EEmmiissssiioonn TToommooggrraapphhyy ((PPEETT)).. Although the first positronscanner was built in 1950, very limited progress was made to advance its usage inmedicine until the 1970s, when the cost of electronic computing became moreaffordable. The revolution in computer technology was a great boon to PET scannerdevelopment: PET scanner design progressed rapidly from a simple 2D detector-arrayto a complicated 3D detector-array with ring geometry.3-11 In the early 1970s, Chesler ofthe MGH physics group developed the filtered back projection technique that laid downthe groundwork for 3D PET image reconstruction.12-14 As a result, noninvasive 3Dquantitative 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 physicsand image reconstruction by Hounsfield.15 Previously, and unrelated to the field ofmedical imaging, Cormack had published papers in the mid 1960s in which hedemonstrated a bench-top x-ray CT scanner with proper image reconstruction based onthe Radon equations.16 In recognition of their work in the development of CT scanning,Hounsfield and Cormack were awarded the Nobel Prize in 1979. Chesler’s filtered backprojection technique for PET was clearly developed in the same time frame as theiterative technique used by Hounsfield and Cormack and is the basis for the currentPET image reconstruction algorithm. Together, these two novel bodies of work havebeen combined to produce modern PET/CT scanning systems.17 For more informationon the history of PET and PET/CT development, there are two very informativewebsites: www.cpspet.com/our_company/history_o_pet.shtml and www.mit.edu/~glb/.

TThhee PPhhyyssiiccss ooff PPEETT.. As noted above, when an emitted positron finally slows down andis attracted by an electron through attractive Coulomb force, they form a positronium.This positronium is very unstable and has a short half-life (10-7sec). It annihilates andyields two high-energy γ rays with energy of 0.511MeV each (equivalent to the mass ofan electron) and nearly 180o apart (conservation of momentum). These two opposingphotons with 180o divergence provide a unique property that enables the quantitation ofpositrons possible in vivo. Figure 1 illustrates this unique property. The probability thatphoton 1 will escape from the medium (p1) is:

p1 = e-µx (1)

The probability that photon 2 (p2) will escape is:p2 = e-µ(D-x) (2)

The probability that both photons will escape is the product of p1 and p2:p1 p2 = e-µx-µ(D-x) = e-µD (3)

where µ is linear attenuation coefficient. It thus suggests by Equation (3) that it makesno difference where the positron is located inside the body, as all positrons annihilateinside the coincidence detection volume (between the dashed lines) and will have thesame probability of being detected. This uniqueness lays down the foundation in usingtransmission scan or a corresponding CT for transmission correction in PET.

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This unique property makes the intensity level shown on the PET image linear andproportional to the concentration of positron emitting isotope in a particular area ofinterest. It also allows us to derive important functional information from PET in regardto disease as well as normal tissue.

Electronic Collimation. Rather than using a collimator to localize a photon’s origin, PETuses coincidence circuitry. Each ring detector is paired with several detectors on theopposite side of the ring to increase detection efficiency. Signal output from each pair ofdetectors is fed into an electronic gating device. The moment that the gating devicereceives a signal, it opens the gate for a predetermined time window to listen to anyincoming 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 inthe counter. The window is usually in the range of a nano-second (10-9 sec), which isderived from D/c (D is the maximum width of the patient body as shown in Figure 1 andc is the speed of light). This timed setting based upon D/c is called the coincidencewindow. The content of the counter is thus the total number of annihilation eventsdetected within a respective detection volume over time. Collimation by coincidencecircuitry is also known as electronic collimation.

Positron Range. When a positron is emitted from its parent nuclide, it carries someinitial kinetic energy. Table 1 lists commonly used positron emitting isotopes, their half-life, their maximum kinetic energy, and their respective stop distance in water. It is thusforeseeable that the location of annihilation can be at some distance away from thelocation of its respective emitting isotope, especially where the isotope is in a low-density region such as a lung.

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FFiigguurree 11.. Schematic diagram illustrates coincidence circuitry, detection volume (between dashed line), andthe traveling distance of respective photons.

Parent Nuclide T1/2 (min) EMax ( MeV ) Stop Distance (mm)15 O 2.05 1.72 0.7 (3.3)13 N 9.9 1.19 0.5 (2.1)11 C 20.4 0.96 0.3 (1.6) 18 F 109.7 0.64 0.2 (0.9)68 Ga 67.7 1.90 1.35 (9.0) 82 Rb 2.25 3.35 2.60 (16.5)

TTaabbllee 11.. 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. Scatteringnot only changes the vector of the radiation, but also its respective energy. This effect isimportant in PET scanning, where we are trying to identify the location of positronannihilation. Two kinds of measurement error due to scattering occur: prompt scatteringand random scattering.

Prompt scattering involves “bending” of the photon tracks by interactions with matterbetween the location of annihilation and the detectors. When annihilation occurs, twogamma rays of 0.511MeV are generated with directions of 180º apart. Before thescanner can detect these photons, however, there is a finite probability that one or bothphotons will interact with traveling medium. Should such an interaction occur, thetraveling course as well as the energy of the respective photon will change. Instead ofstaying on its original course, it will travel a different course as shown in Figure 2. Bothphotons will be detected at nearly the same time (<D/c, where c is the speed of lightand D is the width of medium). Since there is no easy way to know if one or bothphotons has been deflected, the annihilation event of positron Q might bemisinterpreted as happening along the detection volume of BC’ instead of CC’.

Random scattering, on the other hand, involves cases of “mistaken identity” by the ringdetectors. The coincidence window will open once it receives a signal from the oppositedetector. During that window of time, however, there is a reasonable probability that aphoton other than the mate to the initial paired photon from annihilation will hit thedetector 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 asan event occurred inside the detection volume of CC’. The number of these false eventsis proportional to the square of the total activity in the body, and it can be estimatedthrough delaying the opening of coincidence windows.

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FFiigguurree 22.. 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 bylimits regarding the maximum radiation dose the patient is allowed to receive. As notedabove, the number of true coincidence events can be correctly estimated by thefollowing equations:Transmission correction

C’Total = q * CTotal /CTransmission

Scattering correctionCTrue = C’Total - CPrompt - CRandom

where C’Total is the true events if no transmission loss, CTotal is the total measuredevents, CTransmission is the total detected events in a transmission scan, q is anormalization factor, CTrue is the true coincidence events, and CPrompt and CRandom arethe respective events due to accidental prompt and random scattering. To preserve thestatistical quality of C’Total , one requires an almost noise-free transmission scan whichmeans a very long scan time for the transmission scan. CT imaging from PET/CT isused to provide an estimate of transmission correction using an analytical formula tonot only preserve the image qualities but also to significantly shorten the overall studytime.

Motion Artifact. Because of the relatively low sensitivity in detection in comparison withCT, the typical scan time for PET is around 2 to 5 minutes per crystal bed time. Unlessthe imaged organs are stationary, the acquired PET image will be the result of anaveraging among images done at different positions. The resultant image of tumor willtend to be larger than it really is, and also its activity distribution will be skeweddifferently 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 ofmany tumors. Although excellent at helping define anatomy based upon densitydifferences, it provides no physiologic information. In contrast, PET provides uniqueinformation about patient physiology rather than anatomy. The development of PET/CTimaging allows the strengths of each technique to be brought to bear for improvedtarget localization and radiation treatment planning. Proper understanding of theseimaging modalities, including both their advantages and weaknesses, however, isnecessary for proper incorporation into the treatment planning process.

Several commonly used isotopes and their respective radiolabeled compounds arelisted in Table 2. By selecting a specific labeled compound from the table, one canobtain specific physiological information regarding the tumor status.

EE++ IIssoottooppee RRaaddiioollaabbeelleedd CCoommppoouunndd PPrrooppeerrttyy IInnddiiccaattoorr

15O CO2 Blood flowH2O Blood flowO2 Metabolic rate

for oxygen18F FDG Glucose analog Metabolic rate

FLT Fluorothmidine DNA precursor Tumor proliferationFMISO Fluoromisonidazole Hypoxic marker Tumor hypoxiaFDHT Fluorinated steroid Estrogen analog Estrogen receptor FES Fluoroestradiol status

11C Thymidine DNA precursor Tumor proliferationMethionine DNA precursor Tumor proliferationAcetate Choline DNA precursor Metastases

60Cu ATSM Hypoxic marker Tumor hypoxia62Cu methylthiosemicarbazone64Cu

TTaabbllee 22.. Commonly used positron-emitting isotopes, their radiolabeled compounds, and potential applications.

FFDDGG//PPEETT.. Glucose is a major source of energy for the body. With the prospect of PETon the horizon, tremendous research efforts were dedicated to synthesizing a positron-emitting glucose analogue in the 1970s that could be used to measure the metabolicrate of glucose in vivo. By changing the glucose molecular structure slightly and byspecific binding, 2-fluoro-2-deoxy-D-glucose “FDG” is created19 (Figure 3). This FDGmimics standard glucose transport from plasma to tissue, where it can then bephosphorylated to FDG-6-phosphate by the same enzyme (hexokinase) that changesstandard D-glucose to D-glucose-6-phosphate. While D-glucose-6-phosphate continueson 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 intissue. It is the trapping of this metabolic product of FDG in tissue that makes themeasurement of glucose utilization in tissue possible.20 Thus, after FDG injection,detectable positron emission occurs based upon:

a) free FDG in the vasculatureb) 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 floatingabout can be problematic. To help resolve this issue, compartmental analysis is helpfuland provides insights into the ratio of FDG-6-phosphate (signals) to free FDG invasculature and in tissue (background noise).

FFiigguurree 33.. 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).

FFiigguurree 44.. Diagram illustrates the metabolic pathwayfrom D-Glucose to D-Glucose-6-phosphate and thento D-Fructose-6-phosphate. Note that the #2 carbonposition, pointed by red arrow, is wherephosphoglucoisomerase acts on. .

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FFiigguurree 55.. Compartmental model used to describe FDG transport between plasma and tissue. C*P (t), C*E (t), andC*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-6-phosphate can be expressed by the following two equations:

For a steady physiological state, with stable rate constants from the time of FDGinjection to the time of scan, the amount of trapped FDG-6-phosphate will be a goodmeasure 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 atissue:

Therefore, to have measurements that are physiologically meaningful, one needs todetermine 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 scanstart- and stop-times providing the best noise-to-signal ratio may vary from one type oftumor 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 scanis scheduled at a time later than 60 min after initial FDG injection. More studies areneeded 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 thispublication. It is used to delineate not only the primary malignancy but also to helpidentify regional spread of tumor requiring incorporation into treatment fields. Before thecommercial combined PET/CT scanners were available, tumor delineation was doneeither through refined sophisticated image fusion algorithms with treatment planningsoftware or through hand-eye coordination by looking at corresponding PET and CTimages at the same time. With mechanical co-registration between CT and PETdatasets on modern combined units, the CT and PET images obtained at the sametime are automatically co-registered and coded at their respective image header. Anysoftware that is capable of reading the image header, doing the necessary imagemanipulation, 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 radiationoncologist’s daily practice. This software capability allows contour drawing on one set ofimages to be automatically duplicated onto the other set of images and vice versa in alinear fashion.

One of the major benefits in using PET/CT for radiation treatment planning is its abilityto provide better target delineation. Nevertheless, difficulties and pitfalls exist. Thescatter phenomena described above add some geometric uncertainty (up to 4 mm insoft tissue or to 1 to 2 cm in region with low density such as lung) as to the exact originof the positron annihilations. In addition, simply defining and standardizing “abnormaluptake” is problematic in itself. There are several approaches to characterize the extentof tissue FDG uptake. SUV and SUVg (SUV normalized to plasma glucose level)measurements are widely used. However the relatively large variation of SUV amongindividual study subjects and over various time intervals makes these valuationssuspect. Measuring regional metabolic rates for glucose consumption has also beenused for characterizing the target. This procedure, however, requires continuoussampling of FDG in arterial blood, which makes the method impractical in an averageclinical setting. Other clinicians simply use the display intensity to delineate the targetvolume. Caution is in order, however, as the intensity level can be manipulated easilythrough 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 nosimple method of PET-based target delineation has yet been developed. In themeantime, most users opt to err on the side of larger fields with good margins, double-checked with CT anatomic information, and solid clinical judgment.

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References1. 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 toTransaxial 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 emissiontransaxial 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 awhole 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-dimensionalreconstruction 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 Tomographyin 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 emissiontomography”; 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 emissiontomography” 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 NuclearMedicine; 1971, 12:347-348.

13. Chesler D.A.; “Positron tomography and three-dimensional reconstruction technique” in Tomographic Imaging inNuclear 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 ofNuclear 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, withapplications 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 positronemission 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-D-glucose, 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 ShinoharaM.. “The [14C] Deoxyglucose Method for the Measurement of Cerebral Glucose Utilization: Theory, Procedureand Normal Values in the Conscious and Anesthetized Albino Rat”. Journal of Neurochemistry, 1977, Vol. 28,pp.897-976.

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5. RADIOISOTOPESDiane M. Wolinski, Director, North Florida Cyclotron Center, LLC

IInnttrroodduuccttiioonn.. An ever-increasing variety of clinical applications of PET in the areas ofoncology, neurology, and cardiology has encouraged recent increased production ofexisting and novel radiotracers and radiopharmaceuticals. Several routinely producedradiopharmaceuticals are readily available in the United States for relevant PET andPET/CT scans, allowing assessment of glucose metabolism, hypoxia, neuroreceptormapping, blood flow, and unique research applications. Glucose metabolism, inparticular, is used in the diagnosis, staging, and post-therapy evaluation of oncologypatients.13 A listing of those radiolabelled compounds currently used in research,cardiology and neurology shall be mentioned herein; however, the focus of this chapterwill be the background and use of the most common radiopharmaceutical manufacturedto date. Although novel radiotracers continue to be developed to further uniqueapplications in the fields noted above, the vast majority of clinical usage to datecontinues 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. Morerecently, sodium fluoride F 18- injections have been requested for bone scans of selectpatients.

BBaacckkggrroouunndd.. We will focus mainly on the use of FDG in PET imaging for oncologypatients. Although available for research uses over decades, the use of FDG-basedPET scanning did not become popular until its approval for reimbursement by theCenter of Medicare and Medicaid Services (CMS)–previously known as the HealthcareFinance Administration–in the year 2000, when it adopted national coverage policies forseveral [18F]FDG PET procedures related to specific cancers.7

[18F]FDG PET is a radiolabeled analog of glucose that rapidly travels throughout allorgans of the body. It is transported into the cells and phosphorylated at a rateproportional to the rate of glucose utilization within specific tissues. Theradiopharmaceutical cannot exit the cell once phosphorylated by the enzymehexokinase until it is subsequently dephosphorylated by glucose-6-phosphatase. Thereis a delicate balance of retention and clearance of FDG between these mechanisms.Changes in this balance between FDG transport and phosphorylation are used tomeasure and assess glucose metabolism in the organs or tissues.

Accelerated glucose metabolism has been recognized as a cancer recognition tool foryears, but is not specific to cancer. FDG was initially used as a tracer to study brainand heart metabolism. Only later, after several independent studies in the 1980s, didFDG PET imaging become an obvious tool for cancer imaging.8 Specifically, regions ofdecreased or absent uptake of FDG signify decreased or absent glucose metabolismrelative to surrounding organ or tissue background activity. Conversely, increaseduptake in a specific area suggests increased glucose metabolism. In cancer cells,glucose metabolism variations detected by FDG accumulation may be quite extreme:

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FDG accumulation may increase, decrease, or remain normal depending upon the typeof tumor, its stage of development, and its location.

Additionally, glucose metabolism utilizing FDG in biological tissue can identify othercellular dysfunction. For example, it has shown promise in neurological conditions suchas epilepsy, dementia, and Alzheimer’s disease. In cardiology, FDG may be useful inidentifying patients likely to benefit from myocardial revascularization.1 Otherapplications for FDG will be mentioned later in this chapter.

DDeessccrriippttiioonn.. As noted previously, FDG is the common name for theradiopharmaceutical, 2 (fluorine-18) fluoro-2-deoxy-D-glucose (18F-FDG). It is knowncommercially as Fluorodeoxyglucose F18 Injection, USP, a positron-emittingradiopharmaceutical containing radioactive 2-deoxy-2-[18F] fluoro-D-glucose: usuallyabbreviated as [18F]FDG , or simply FDG. The isotope is administered via rapidintravenous infusion. This isotonic drug is packaged in a sterile, pyrogen-free, multiple-dose 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 C8H11

18FO5,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 amountof 18F expressed in MBq (mCi) per mL at the time indicated in the labeling. It may containsuitable preservative and/or stabilizing agents. Additional information regardingpackaging, storage, and labeling may be found in the current USP.3

MMaannuuffaaccttuurree.. Producing recovered 18F from an aqueous solution of (H2O/18F-) isachieved by proton bombardment of enriched water, (18O), in a GE Medical SystemsMiniTrace cyclotron, utilizing a nuclear reaction, 18O(p,n)18F, and finally is extracted byion-exchange chromatography using a synthesis unit such as a GE Medical SystemMX. It can then be solvated organically and, through nucleophilic substitution,specifically combined into radiopharmaceutical applications. Essentially, it ismanufactured with nucleophilic substitution of [Kryptofix 2.2.2]18F– with thecorresponding protected precursor. Mannopyranose, in the form of itstrifluoromethansulfonyl 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 yieldruns consistently around 65% of the initial F-18 activity. A full process production runencompasses approximately 3 1/2 hours. Step one, F-18 production, may typically takefrom 30 to 130 minutes dependent upon the final FDG radiopharmaceutical required forthe day. Step two, post F-18 delivery to the synthesis unit and the synthesis itself, iscompleted in approximately 32 minutes.

QQuuaalliittyy CCoonnttrrooll.. Currently, all compounds like FDG that carry a radioisotope used forPET imaging require Food and Drug Administration (FDA) approval.14 Appropriatecriteria and procedures to evaluate PET products for safety and effectiveness are stillunder 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 couldcurrently support the approval of some commonly used PET radiopharmaceuticals. TheUSP testing methods for FDG are the only current testing standards recommended. Abattery of quality-control tests is referenced in the Pharmacopeia within the officialmonograph for FDG injection. These tests include radionuclide identification of agamma-ray spectrum at 0.511 MeV and a possible reflective peak at 1.02 MeV. Its half-life is listed as a range of 105 to 115 minutes. A chromatogram of the product solutionshall be not more than 10% of a prepared standard. No more than 175/V USPendotoxin unit per mL of the Injection is contained at expiration time. The listed pH is4.5-8.5, 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 thetotal assay for radioactivity listed as MBq or mCi per mL. A post-release sterility test (14days duration) shall be performed.3

DDrruugg HHaannddlliinngg aanndd DDiissppoossaall.. Prior to administration, the vial is visually inspected fordiscoloration and particulate matter. It must be disposed of in a safe, compliant mannerwithin applicable nuclear regulations if the drug has indication of unsuitability or visualcontamination. Suitable garments are worn to protect hands and eyes, and appropriateprotective shielding for 511 keV gamma exposure is used. The specific gamma rayconstant 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 an8.3 mm thickness of Pb, with a coefficient of attenuation of 0.25, decreases externalradiation exposure by 75%. Needless exposure to technologists, patients, and othernearby persons is to be avoided. Only employees with appropriate training inradionuclide handling, including physicians, technologists, and ancillary personnel whoare approved by the appropriate agencies to use these radionuclides, shall be inproximity to the drug.

AAddmmiinniissttrraattiioonn.. Preparation of the patient by prior instruction should includediscussion of the effects of fasting, varying blood sugar level, glucose intolerance,diabetes, activity and exercise prior to PET scan utilizing FDG; proximity tochildren/pregnant women post injection; notification of pregnancy or possiblepregnancy; liquid intake (to hydrate the patient prior to drug administration); and otherinstruction by the physician or nurse as indicated. A measurement of blood glucoselevel immediately prior to the injection is an important part of the process to assureminimal adverse reaction of the patient due to the fact that this isotope is, genericallyspeaking, “radioactive sugar water.” The FDG is typically administered as a unit doseinjection of 10 to 15mCi calibrated at injection time. The optimum time for a PET scan isusually achieved 30 to 40 minutes after injection.4

Utilizing the current technology of the PET/CT scanner, the typical whole-body scanutilizing the radiopharmaceutical FDG will be complete in less than 30 minutes,exclusive of preparation time. For most procedures, a single scan is required foracquisition. However, in evaluating pulmonary nodules or assessing mediastinaladenopathy, a second scan may be requested by the physician.10 The second

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procedure does not require a second injection of the radiopharmaceutical, as the FDGcontinues to circulate throughout the body several hours after injection.11 FDG iseventually cleared from most tissues within 24 hours, and eliminated in the urine. Drug-drug interactions and overdoses have not been reported.6

LLiimmiittaattiioonnss.. FDG PET does not work equally well for all tumors. Indications for themost effective use of PET are evolving. Although FDG is the most commonly usedtracer for cancer imaging, there are some well-known limitations to its use. Theseinclude effective limits of resolution of approximately 5 mm in size, inability toconsistently differentiate between inflammation and malignancy, difficulty visualizingbrain 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 toincreased FDG uptake.5 Similarly, fungal infections and benign tumors with patterns ofincreased glucose metabolism may result in false-positive exams. A negative resultdoes not preclude the diagnosis of cancer. FDG competes with glucose for uptake intissues. 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 glucosedue to lower renal re-absorption of FDG than glucose. Diabetic patients can thereforehave low FDG uptake in tumors if their serum glucose levels are high. If proliferationrate imaging is desired, FDG may not be the best option due to its comparable uptaketo the cell cycle.12 Lastly, the drug’s half life is a short two hours–its usefulness istherefore limited by the need for daily “on time” production and mandatory rapid deliveryjust prior to injection time. It is literally a race against the clock to synthesize theradiopharmaceutical, 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 closeproximity to take full advantage of the synthesized product.

OOtthheerr aapppplliiccaattiioonnss ooff PPEETT rraaddiioopphhaarrmmaacceeuuttiiccaallss.. Promising applications for PETmay lie within the fields of neurology and cardiology. FDG is increasingly utilized as atool in evaluation of neurodegenerative conditions as well as in diagnosis andmanagement of these disorders. In the brain, early clinical intervention after the positivediagnosis of Alzheimer’s disease via FDG-based PET imaging is possible. Brain tumorsmay be located and distinguished from scar tissue, and a more accurate assessment intumor and other sites in the brain suitable for delicate surgery may be achieved. Amyriad of investigative tools including FDG is used to identify focal epilepsy, refractoryepilepsy, and Parkinson’s disease. Other conditions such as fronto-temporal dementia(FTD), primary progressive aphasia (PPA), semantic dementia (SD), progressiveprosopagnosia (PP), and progressive visuospatial dysfunction (PVD) may have alteredFDG uptake as well.

In the heart, PET may be beneficial in mapping out appropriate heart surgery bypassfields after a myocardial infarction. Prior to an infarction, PET can quantify the extent ofheart disease.2 Using N-13 ammonia, qualitative and quantitative regional coronaryblood flow and metabolism can be measured. Dysfunction, via the absence of ongoingmetabolism 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 patientswith osteogenic sarcoma ie, a malignant bone cancer.15 Bone scan tomography with 3Dwhole-body imaging using the PET/CT scanner produces a superior image to otherimaging modes. It may be useful in assessing bone perfusion, regional bone pathology,or metastatic disease in the skeletal system.

CCuurrrreenntt PPoossiittrroonn IIssoottooppee PPrroodduuccttiioonn.. Four basic positron-emitting radionuclidecompounds 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 aqueoussolution of (H2O/18F-) and finally extracted by ion-exchange chromatography. It can then be solvated organically and, through nucleophilic substitution, utilized inradiopharmaceutical production. An alternate method of production using electrophilicsubstitution resulting in a radioactive gas is rarely performed.1 Fluorine-18 decays bypositron emission. The principal photons useful for diagnostic imaging are the 511 keVgamma photons produced by positron annihilation resulting from the interaction of theemitted positron with an electron.Radiopharmaceuticals using this tracer and their usefulness in biomedical applicationinclude: [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 anuclear reaction, 16O(p,α)13N. To minimize in-target oxidation, a scavenger such asethanol may be used. There is no further chemistry involved in its production.Radiopharmaceuticals using this tracer and their usefulness in biomedical applicationinclude: [13N]ammonia (myocardial blood flow).1

Carbon-11 is produced by proton bombardment of natural nitrogen through the nuclearreaction on 14N(d.n)15O. Oxygen -15 can be produced as molecular oxygen (15O2) bymixing the target gas with 5% natural carbon dioxide as a carrier, or directly as carbondioxide (C15O2). By reduction of C15O2 on activated charcoal at 900°C, carbon monoxide(C15O) can also be easily produced. A great limitation of this isotope is its relativelyshort half life (t 1/2=20 min.). Theoretically, with 11C, any organic molecule could belabeled by isotopic substitution of 11C for natural carbon, retaining the full properties ofthe parent molecule. Unfortunately, the short half-life of this radioisotope createslimitations: The multi-step synthesis processes to create the radiopharmaceuticals endwith a low yield of product for the effort. Radiopharmaceuticals using this tracer andtheir usefulness in biomedical applications include: [11C]SCH23390 (dopamine DIreceptor), [11C]flumazenil (central benzodiazepine receptor), [11C]PK11195 (peripheralbenzodiazepine receptor), [11C]PIB (amyloid plaque: Alzheimer’s disease), [11C]AG1478

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(EGF receptors), [11C]choline (biosynthesis of phospholipids), [11C]methionine (aminoacid metabolism/brain, head/neck, lung, breast, prostate, urinary bladder tumors),[11C]tyrsine (amino acid metabolism/brain tumors (C11-tyrosine), [11C]5HTP (serotoninlevels/neuroendocrine gastrointestinal tumors), [11C]L-DEP (monoamine oxidase Benzyme levels/pituitary tumors), [11C]L-DOPA (dopamine levels/neuroendocrinepancreatic tumors), [15C]O2 (blood flow/brain tumors), [15C]O (blood volume/braintumors), [11C]AG957 (BCR-abl receptors).13,14

Oxygen-15 is produced by deuteron bombardment of natural nitrogen through the14N(d,n)15O nuclear reaction. Molecular oxygen (15O2) production or direct production ascarbon dioxide (C15O2) can be produced via mixing target gas with 5 percent naturalcarbon dioxide as a carrier. Additionally, carbon monoxide (C15O) can be produced easilyby reducing carbon dioxide (C15O2) on activated charcoal at 900°C. 15O2 - oxygen can bedirectly produced out of the target without further chemistry. Radiopharmaceuticals usingthis tracer and their usefulness in biomedical applications include: [15O]oxygen (oxygenmetabolism/brain tumors), [15O]carbon monoxide (blood volume/brain tumors),[15O]carbon dioxide (blood flow), [15O]water (H215O) (blood flow).13,14

IInnvveessttiiggaattiioonnaall IIssoottooppeess aanndd PPootteennttiiaall AApppplliiccaattiioonnss.. Researchers are designing newradiopharmaceuticals as innovative solutions to today’s limited PET imagingapplications. 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 notappear to be a “universal” PET radiopharmaceutical suitable for all types of tumors inthe field of oncology, nor for cardiology or neurology applications. However, the study ofresearch-level investigational isotopes continues to push forward the horizons of novelapplications. Although limited studies and evaluation of patients utilizing the followingradioisotopes and radiopharmaceuticals have been performed to date, continuedcollection of data from larger patient studies is critical to the development ofappropriate radioisotopes for future drug approvals. A limited list of research-gradetracers follows. Additionally, the use of sodium fluoride F18- has been used as animaging agent in the study of patients to define areas of altered osteogenic activity.

SSooddiiuumm FFlluuoorriiddee FF1188--..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 chlorideand a calibrated amount of sodium [18F] fluoride. Its decay is similar to FDG with apositron 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 bonecrystal from the plasma and is taken up in bone in proportion to blood flow and bonemetabolic activity. Since skeletal uptake of the [18F]fluoride ion is altered in areas ofabnormal osteogenesis, visualization of osseous lesions is possible.16,17

The greater deposition of ‘F18-’ accumulates in the skeleton symmetrically in the axialregion, the bones around joints, fracture site, and in bones affected by fibrous

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dysplasia, osteomyelitis, Paget’s disease, spondylitis tuberculosis, hyperostosis frontalisinterna, tumors, myositis ossificans, and ephiphyses.18,19 Less accumulation occurs inthe shafts of long bones and appendicular skeleton.

Radiotracer Applications

18F-Fluoromisonidazole (18FMISO) hypoxia/brain tumors, ischaemic penumbra/stroke1

H215O , 15O2, and C15O2 sequential cerebral blood-flow studies,

oxygen consumption, cerebralprofusion quantification in ischaemic stroke, quantification of brain function, parietal lobe function, working memory processing1

13N-ammonia qualitative/quantitative regional coronary blood flow in evaluation/coronary artery disease1

(recently approved for production - limitation of short half-life)

11C-flumazenil quantify cerebral benzodiazepine receptors/psychiatric, panic, traumatic stress disorders1

18F-Fluorocholine brain tumors, ovarian cancer, prostate cancer, metastisis to pelvic lymph, bones 9

SSuummmmaarryy.. The use of FDG PET has had a considerable positive effect on themanagement of oncology patients. PET has demonstrated its usefulness as animaging modality if utilized for specific applications with select patients. In spite of itscurrent limitations, metabolically active diseases can be tracked using this tool. As newradiotracers are developed, and as approval for their use becomes more widespread, itis clear that the ability to image and manage additional cancer types will broaden thescope of PET imaging’s 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 18F-

FDG PET for the Evaluation of Pulmonary Nodules. J. Nucl. Med: 2002:43:7, 871-875.11. Lodge, MA, Lucas, JD, Marsden, PK, Cronin, BF, O’Doherty, 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-deoxy-

2-(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.htm15. 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 ProcessJohn Wells, Jr. MS MD, Brian Thorndyke, PhD, and Allison Grow, PhD, MD

In an era when radiation oncologists routinely try to restrict CTs/PTVs/treatmentvolumes in order to minimize toxicities and escalate dose, prudence mandates constantefforts to minimize PET/CT simulation errors as well as straightforward methods tocontour PET/CT volumes. This chapter focuses on three factors which we considerimportant in the development of PET/CT fusion based treatment planning programs.They are scanner setup, education of the PET/CT staff regarding proper patientpositioning/scanner settings, and dosimetric rules for contouring PET-defined volumesof interest.

SSccaannnneerr SSeettuupp.. It is important to use the scanner’s flat board insert. Patientsscanned on a concave couch and treated on a flat table are at risk for uncorrectablesetup errors. In addition, it should be noted that small pitch deflections can occurwhen the concave scanning couch is fully extended. By strengthening the couch thiseffect is minimized.

The scanner’s internal fixed lasers can be used to define isocentric entry points.However, when your patient’s isocenter needs to be near the surface, the internallasers may be rendered useless as it may be impossible to shift the couch to bring theinternal lasers to bear. In addition, based on the patient’s size and surface topography,it may be difficult to visualize and mark the three isocentric entry points. Solutions tothis problem may be achieved by marking and placing BBs on the patient at the time oftraditional or CT simulation prior to PET/CT scanning, or through the use of an externallaser system (we use Lap Link) focused on the scanner to generate the three isocentriclanding points. In our practice, we use our Lap Laser system to mark the patient’sisocentric entry points after which BBs are placed and the patient immediatelyscanned.

Prior to leaving the room, it is important for the CT tech to “zero” the couch on theisocenter. Failure to so do may create treatment plan display problems.

When PET/CT scans are being processed for use in treatment planning, one shouldensure that the PET slice count equals the CT slice count by using a transformedimage set. PET/CT staff should be instructed to provide you with this data set which willensure proper coregistration of images for planning purposes.

When the PET and CT images are acquired on the same scanner (eg, SiemensBiograph PET/CT, or GE Discovery ST PET/CT), it is assumed that the patient hasremained in the same position throughout both scans, and thus the PET and CT seriescan be coregistered automatically based on DICOM coordinates. To ensure that thePET 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 inspectionof PET images superimposed on CT, or by identifying landmarks and applyingcorresponding software translations and rotations. Finally, whether fusion is hardware-or software-based, one can always affix radio-opaque PET fiducials to the patient toprovide additional verification of PET/CT alignment prior to contouring.

PPaattiieenntt PPoossiittiioonniinngg IInnssttrruuccttiioonnss.. Unless you are fortunate enough to have a PET/CTscanner in your department, your planning scan will be performed outside of yourdepartment down the hall or down the street. In the later two situations, it is importantto educate the facility’s staff prior to asking them to perform your scans. Their nuclearmedicine and/or CT backgrounds do not prepare them for radiation oncology’s precisionpositioning requirements.

In our experience, it is best to send a dosimetrist to the procedure to make sure thestudy is correctly performed. While minor variations in roll, pitch, and yaw are notimportant from a diagnostic perspective, they are critical to ours as it is impossible tocorrect for these errors on the planning computer. The dosimetrist assistance in theplacement of treatment aids such as masks, molds, straps, foot braces, etc isinvaluable. Prior to leaving the PET/CT room before scanning, the dosimetrist shouldcheck the isocentric marks/BBs one last time to make sure they neither wash nor fall offprior to treatment.

CCoonnttoouurriinngg RReeccoommmmeennddaattiioonnss.. We do not view PET-derived volumes as preciserepresentations of targets of interest. We use the coregistered CT for this. We usePET-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 arereduced 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 focalcontouring stations to PET only to optimize the visual display.

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With respect to contour itself, werecommend that you draw your margin 4 to5 mm beyond the visible border of the PETpositive site you want to contour. This “fudgefactor” accounts for limits of resolution dueto photon non-colinearity, which is in therange of four mm. Since a clump of 1 millioncancer cells can fit on a pinhead, while theymight contribute photons that enhance thevisualized border you see, by itself, thisclump will not visualize. Ergo, our fudge

factor. As an aside, we draw our fields based on traditional CT-based field design whichhas been modified to include PET data as we are concerned about geographic missesby planning only PET positivity.

FFuuttuurree DDeevveellooppmmeenntt.. In the next few years, automated SUV-based contouring systemswill come on the market that should significantly reduce contouring time. Theseapplications will likely rely on minimum and maximum thresholds to determine PETvolumes within a region of interest, similar to currently available algorithms for auto-segmenting CT structures. There are additional hurdles for PET segmentation, however,since radiotracer activities (whether absolute or SUV-normalized) characterizing amalignant lesion are not well established. Indeed, it may be the case that theappropriate threshold for a given malignancy is site-, stage-, and patient-specific. Someresearch involving mouse models has suggested it may be fairly accurate to delineatean 18FDG-PET volume by selecting all neighboring voxels with an intensityapproximately 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 sophisticatedstatistical and physiological modeling, which will become available as data isincreasingly accumulated from manual PET/CT based contouring.

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7. LUNG CANCERAnand M. Kuruvilla, MD, FACRO, A. Craig Collie, MD, David W. Graham, Jr., MD

Introduction of PET/CT scanning into the radiation oncologist’s armamentarium hasbegun to play a major role in today’s therapeutic interventions for lung cancer. In almosttwo thirds of patients analyzed in one study, PET/CT scanning influenced treatmentintent, 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 EnhancedPET/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 moreaccurate patient staging, and subsequent treatment with radical radiation therapy aloneor in combination with chemotherapy.2 Bradley, et. al. from Washington Universityrecently reported FDG PET/CT altered AJCC TNM Stage in 31% and altered theradiation therapy volume in 58% of the patients studied.3

CT-based 3D conformal radiation treatment planning in lung cancer is based upon theexcellent imaging of lung and mediastinal structures where both tumor and normaltissues are well delineated anatomically. Most importantly, CT provides electrondensities of the relevant tissues, with which radiation therapy planning softwarecomputes dose distribution. Current generation scanners that combine the twomodalities, use the CT component for PET attenuation correction, in addition tolocalization.

Most NSCLCa patients will require a combined modality treatment plan includingradiation therapy and chemotherapy, with or without surgery. We make every attempt tofacilitate early consultation with both medical and radiation oncologists during the initialstaging work-up. Such early involvement and coordination is imperative to facilitateneedless duplication of effort, and allows staging procedures such as the PET/CT to bedone in the treatment position, so that the data collected can be used not only forstaging, but also for direct input into the radiation therapy treatment planning system.

Appropriate consents are obtained during the initial consultation. The patient thenundergoes “a pre-simulation process.” Typically, patients are placed in a supine positionon the simulation couch (fl at table) with arms overhead, and the simulationtechnologist then fabricates a comfortable immobilization device, (Alpha cradle) whichis able to readily fit into the PET/CT bore. After reviewing the relevant availablediagnostic imaging studies, the radiation oncologist fluoroscopically encompasses theareas involved as well as the adjacent echelons at risk, with generous margins. Theradiation oncologist also takes this fluoroscopic opportunity to crudely but relativelyeffectively visualize the extent of normal motion on the relevant structures. While in thestandard simulator, anterior and lateral laser points (at d1/2) are marked with indeliblemarkers and covered with Tegaderm. AP and lateral orthogonal films centered on thesepoints 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 thesimulation and treatment suites, to ensure reproducibility and consistency of patient setup. To facilitate this, the simulation technologist assists the PET/CT technologist in theset up of the patient in a manner that geometrically mimics the parameters in thesimulation and treatment suites.

Prior to whole-body PET/CT, bb markers are placed on the orthogonal marks notedabove for the CT portion of the scan, and are subsequently replaced by FDG markersfor the whole-body PET study that typically scans from the base of skull to the mid-thighs. The non-contrast planning chest CT uses 3 mm slice thickness scans from thelevel of the hyoid superiorly to L1/L2 interspace inferiorly to ensure the lung bases areimaged. Recently, an additional delayed PET/CT scan protocol is performed one hourafter the first PET/CT to unmask potentially involved nodes; increasing SUV uptake inthese nodal groups on the delayed study is considered to signify involvement (Figures 1and 2). It is expected that inclusion of these nodal groups in the treatment portals willreduce the risk of geographical misses. Following completion of the study, the radiationoncologist reviews the combined study with the diagnostic radiologist, who in our caseis also a nuclear medicine physician, to clarify pathologic involvement. SUVs thatcompare FDG uptake of tissues of interest to normal liver SUV levels are particularlyuseful (SUV levels higher than background liver is suspicious for tumor involvement).

The combined review is symbiotic as getting feedback on the clinical history enablesthe radiologist to generate a comprehensive report while the radiation oncologist learnsnormal artifacts that could otherwise easily be mistaken and contoured as tumor FDGuptake; ‘brown fat’ in the supra clavicular area or mediastinum can easily be mistakenfor 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 oforigin. The diagnostic radiologist can also help the radiation oncologist differentiatenormal vasculature and mediastinal contents from pathologic areas.

With time and experience, radiation oncologists can quickly develop the expertise tomanipulate the intensity threshold of PET fusion images brought into the radiationtherapy treatment planning system software, to help with tumor-volume contouring. Onetypically starts contouring with the images at 40% of maximum intensity to helpdelineate 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 treatmentvolumes today typically include the FDG-avid primary tumor and nodal volumes. Inaddition, any nodes enlarged by CT criteria (> 1 cm) are included in the clinical targetvolume (CTV). Typically a 1 to 2 cm Planning Target Volume (PTV) margin is extendedbeyond the CTV to further prevent geographical misses, and even more volume isincluded as needed to allow for respiratory motion. Of interest, the fact that the PETimage is acquired over several minutes ensures that the “hot spot” of uptakerepresenting 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 moreconfident of the true volume of tissue requiring treatment by contouring the FDG-avidareas and thereby accounting for a large component of the 3D respiratory motion (seecase presentation in Figures 3A-3E).

The challenge in treating lung cancer has always been how to safely increase thetumor dose while minimizing normal tissue irradiation. Additionally, the focus today isto achieve full doses of chemotherapy to be administered concomitantly withradiation. IMRT lung irradiation helps facilitate this end by reducing esophagealirradiation while at the same time keeping the spinal cord, cardiac and lung volumeswithin tolerance limits.

Gating technologies are maturing but are far from being perfected. We have recentlybeen using PET/CT images with our planning software to determine the extent ofmotion artifact. The following protocol is employed: The initial PET/CT scan iscompleted, 45 minutes after FDG administration; subsequently, in selected cases, asecond delayed PET/CT study is performed one hour later, through the chest bedposition only. This “free breathing” study is done with the patient instructed to breathnormally, i.e., with tidal breathing and no breath hold. Two final chest CT studies withlimited 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 mostpatients can maintain a limited breath hold for 10-15 seconds during each scan. Theradiation oncologist typically will pick the delayed CT to be the primary set for treatmentplanning. The delayed CT and delayed PET scan are then “transformed,” which is reallythe process of co-registering their distinct origins within Siemens Biograph™ e.softsoftware. This process essentially locks these two DICOM image sets so that they areaccurately and reliably fused and are then imported into our planning software. The CTis imported as the primary DICOM data set while the PET is the secondary DICOMdata 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. Thisvolume is called the free breathing GTV. Once this is completed, the PET scan isdiscarded and the free breathing primary CT is then fused to the Inspiration CT (whichnow replaces the PET data set as the secondary data set) and GTV Inspiration is thencontoured on each axial image and finally, the last GTV expiration set is contouredwhen the CT expiration is fused to the free breathing CT using the above describedmethodology.

Figure 4A & 4B shows these three GTVs that encompass the tumor surrounded by aplanning tumor volume (PTV). We currently use this methodology to attempt to gaugethe 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 twistingdistortion. Chest wall, diaphragm, and mediastinal extension does limit some of themotion, but with the advent of 4D imaging technologies it is evident that thesemovements can still be quite substantial. Multiple vendors are coming out with gatingsolutions but, in the interim, we are using the above methods in carefully selectedpatients with IMRT particularly when it is clear that the IMRT dosimetry in thesesituations is far superior to any 3D conformal option.

Table 1 outlines the guidelines used by the FROG with regards to normal tissue dosesand volumes when doing an IMRT plan for lung cancer.4,5,6,7 The radiation oncologistassesses the extent of motion in each case during treatment planning to assessfeasibility and typically the dosimetrist attempts to generate the best 3D conformal planin each case that is compared to the IMRT plan to verify the benefit of using IMRT inthe case.

Figures 5A - 5D are images pertaining to a 61-year-old lady with a 6 cm non-small-celllung cancer involving the superior segment of the left lower lobe, Stage II B, T3 NO MOper PET/CT and treatment with concomitant chemoradiotherapy as she was medicallyinoperable. Low-dose weekly Carbo/Taxol was delivered with IMRT to 5940 cGy. Theinitial volume included the lingular chest wall primary tumor, with left hilar andmediastinal nodal echelons at risk and her treatment included a 5-beam IMRT plan in25 fractions. Primary and nodal regions both received 180 cGy per day. After the initial45 Gy and radiation was continued to the GTV alone with 3 IMRT beams with anadditional 1440 cGy in 8 fractions. The main advantage with this approach is that, inaddition to sparing the heart, spinal cord, and protecting her normal lung, the patienthad minimal esophagitis during treatment and could complete the prescribed coursewith no interruption.

Studies may eventually prove the relative safety of higher doses, but we still currentlyprescribe 60 to 66 Gy as the norm. Recent results of the RTOG 9311 dose escalationstudy with 3D CRT, with or without neo-adjuvant chemotherapy only, noted that theradiation 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%.88

The majority of non-small-cell lung cancers today require concomitantchemoradiotherapy. Already there is reliable data becoming available that the bestresults attainable today will be with full doses of chemotherapy with concomitantirradiation. 9 We now have the tools in our armamentarium to help our patients achievethis end.

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FFiigguurree 11.. 58-year-old male presented with a cough. Imaging demonstrates 8 cm right apical paravertebral mass.

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FFiigguurree 22.. Standard PET/CT imaging acquired 45 minutes after FDG administration does not show any FDG activityin the mediastinum (A), whereas delayed scan 1 hour later does reveal mediastinal FDG uptake indicating involvedmediastinal lymph nodes (B).

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(B)

(A)

FFiigguurree 33AA.. 80-year-old medically inoperable patient with poorly differentiated squamous-cell carcinoma of thebronchus intermedius. Mediastinoscopy was negative. PET/CT confirmed right infrahilar FDG-avid mass (maximumSUV 15.2) with associated right lower lobe segmental atelectasis posterior to the central mass. One hour delayedimaging also confirmed lack of FDG-avid mediastinal nodes.

FFiigguurree 33BB.. Image demonstrates ability of PET to delineate FDG avid tumor from atelectasis, thereby providing anopportunity to minimize normal tissue irradiation.

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FFiigguurree 33CC.. The patient was treated concomitantly with radiosensitizing carboplatin and Taxol along with 5-field IMRTusing 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) IMRTtreatment facilitated by PET/CT imaging allows the high radiation dose to wrap around the spinal cord.

FFiigguurree 33DD.. To protect lung function, beam arrangements are selected to limit a maximum of 22% of the lung to 20Gy. Attempts are made to minimize cardiac irradiation and injury as well.

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FFiigguurree 33EE.. Post-treatment PET/CT 1 week following radiation treatment demonstrates near-complete resolution ofabnormal FDG uptake. In light of good response, current chemotherapy regimen was continued for another 2 cycles.

FFiigguurree 44AA:: Stage III A, right upper lobe adeno carcinoma with FDG avid enlarged right para tracheal nodes alsoquestionable FDG uptake in right scalene seen on delayed scan. Axial composite of free breathing CT, showing GTVfree 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 1cm PTV, encompassing all GTVs.

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

FFiigguurree 44BB.. 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 prescribedpreoperatively 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 2additional cycles of full-dose chemotherapy.

FFiigguurree 55AA.. PET/CT demonstrating T3 N0 M0 (Stage II B lesion).

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FFiigguurree 55BB//CC.. Axial CT with fused free breathing, expiration and inspiration GTVs demonstrate minimal movementencompassed by PTV. DRR to right depicts primary tumor treated to 59.4 Gy and nodes to 45 Gy.

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FFiigguurree 55DD.. DVH demonstrates primary 59.4Gy, nodes 45 Gy, spinal cord < 40Gy, lungsV20 < 37%, esophagus V55 < 30%.

TTaabbllee 11.. Suggested target and normal tissue doses for lung cancer.

SSuuggggeesstteedd TTaarrggeett aanndd NNoorrmmaall TTiissssuuee DDoosseess:: LLuunngg CCaanncceerr

GGTTVV:: Gross tumor from PET &/or CT.

CCTTVV:: 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 beyondthe furthest involved nodal station.

PPTTVV:: CTV + 0.5—1 cm. Dose to PTV: from -7% to +15%.

NNoorrmmaall TTiissssuuee TToolleerraannccee DDoosseess

LLuunngg:: V20 < 37% of total lung volume. (total lung volume = volume of both lungs minus PTV, and V20 is volumereceiving > 20 Gy). Strive to keep individual Lung V20 < 22 %.

SSppiinnaall CCoorrdd:: Global max and dose at any point not to exceed 40 Gy. Contour entire vertebral canal as cord, and thanadd a 1 cm margin, which is what we define as “cord plus 1 cm.” This rule should not be violated.

EEssoopphhaagguuss:: V55 should be < 30%. Mean esophageal dose < 32 Gy. Note: Contour entire esophagus from larynx toG.E junction.

HHeeaarrtt:: V50 should be < 40%. Whole heart < 40 Gy.

66 MMeevv PPhhoottoonnss uusseedd wwiitthh ccoorrrreeccttiioonn ffaaccttoorrss uunnlleessss ootthheerrwwiissee ssppeecciiffiieedd

8. Head and Neck CancerApril Mendoza, MD, and Michael Sinopoli, MD

IInnttrroodduuccttiioonn.. Primary head and neck cancer can arise from anywhere in the mucosallining of the upper aerodigestive tract. Squamous cell carcinoma is the most commonhistology and is often associated with tobacco and alcohol use. For many years, radiationwas reserved for locally advanced and unresectable tumors. More recently, with anincreased focus on functional outcomes and organ preservation, radiation with or withoutconcurrent chemotherapy is considered the standard of care for many subsites. Due toextensive lymphatic drainage pathways, head and neck cancers tend to metastasize toregional nodes in somewhat predictable patterns. PET imaging can greatly help inidentifying metastatic lymph nodes, as well as the extent of the primary lesion.

IInniittiiaall SSttaaggiinngg.. 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 PETfor accurately staging cervical lymph nodes ranges from 82% to 88% and specificityfrom 94% to 100%. This is a marked improvement over CT and MRI with sensitivitiesand specificities of 65% to 88% and 41% to 47%, respectively.2 Detection of the primarysite is accurate in 88% to 98% of cases, and in cases of metastatic cervical nodes froman unknown primary, PET can reveal an otherwise clinically undetectable lesion in up to20% of cases.3 One significant advantage of PET over other imaging modalities is theability to stage a primary lesion and regional nodes, while simultaneously searching fordistant metastases and a possible synchronous primary lung cancer.

TTrreeaattmmeenntt PPllaannnniinngg.. Radiation treatment planning for head and neck cancer typicallyinvolves obtaining CT scans or radiographs with the patient positioned in appropriateimmobilization devices such as thermoplastic masks. The ability of newer generationPET/CT scanners to acquire complete whole-body scans for both staging and treatmentplanning in a single setting within 20 minutes greatly enhances patient comfort andconvenience.

Fused anatomic and metabolic images are invaluable for GTV delineation during thetreatment planning process. IMRT is often utilized in head and neck cancer for maximalnormal tissue sparing. Parotid sparing is of primary importance in minimizing chronicxerostomia and improving quality of life. By utilizing PET/CT fusion, one studydemonstrated concordant GTV volume in 89% of patients based on clinical andconventional imaging compared to PET activity in the primary site. This allowedmaximal parotid sparing in 71% of patients where there was no PET activity near theparotids.4 Another study demonstrated that PET/CT data were critical in altering theradiation treatment plan in 31% of patients compared to traditional imaging. Themajority of the changes were due to upstaging of the primary or detection of cervicalmetastases.5

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Future trends in molecular- and hypoxia-targeted therapy will utilize metabolic scanningto select targeted systemic therapy or guide higher-dose regions in radiation treatmentfields. Fused Cu-ATSM PET/CT images have been utilized to plan IMRT integrated highdose boost regions within hypoxic areas of primary head and neck tumors. 6

RReessppoonnssee ttoo TTrreeaattmmeenntt.. The optimal utilization and timing of post-treatment PET/CTscans for evaluation of response and prediction of outcome has yet to be defined.Several studies have demonstrated that pretreatment SUV values correlate withdisease-free survival, with high values predictive of worse outcome.7 The use of PETCT for detection of residual disease or recurrence has a high sensitivity but moderatespecificity due to false-positive readings at sites of post-surgical or post-radiationinflammation. Timing of the follow-up scan has a significant effect on accuracy. Themost accurate window for detection of true residual or recurrent tumor appears to bebetween three and four months after completion of radiation. PET evaluation of residuallymphadenopathy following radiation or chemoradiation is valuable in identifyingpatients who may avoid a neck dissection. Post-treatment PET at 12 weeks follow-uphad a negative predictive value of 100% in one study, with no local failures in neckswith residual detectable nodes but negative PET scans which were observed withoutsalvage neck dissection.8

CCoonncclluussiioonn.. 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/CTresponse has been shown to correlate with outcome. Furthermore, it helps selectpatients with residual cervical nodes who may forego neck dissection. PET/CT definitionof radiation treatment volume allows for dose escalation within the tumor volume usingIMRT integrated boost technique. Future integration of hypoxic or molecular imaging willfurther 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, 19982. 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 HeadNeck Surg 125:1322-1328, 1999.

3. Fogarty GB, Peters LJ, Stewart J: The usefulness of fluorine 18-labelled deoxyglucose positron emissiontomography in the investigation of patients with cervical lymphadenopathy from an unknown primary tumor. HeadNeck 25: 138-145, 2003.

4. Nishioka T, Shiga T, Shirato H: Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning oforopharyngeal 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, TufanoRP. The role of positron emission tomography and computed tomography fusion in the management of early-stageand advanced-stage primary head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 132:12-16, 2006.

6. Chao KS, Bosch WR, Mutic S: A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guidedintensity-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 radiationtreatment. IJROBP 63:991-9, 2005.

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9. Breast CancerSonja Schoeppel, MD

IInnttrroodduuccttiioonn.. Breast cancer is the most common cancer in women, accounting for onethird of all cancer cases among women in the United States and causing approximately40,000 deaths annually1.

Accurate staging of disease extent is a major determinant of appropriate treatmentrecommendations. PET/CT is a Medicare-approved indication for the initial staging andfollow-up of patients with breast cancer. It is a more sensitive and specific identifier ofmalignant tissue in the breast than CT or MRI .2-4 In addition, a recently publishedretrospective 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 inassessing the extent of disease (local tumor burden, lymph node involvement, anddistant metastasis) than either modality alone or side-by-side5.

This chapter will explore the uses of PET/CT in the clinical practice of radiationoncology pertaining to breast cancer management. First, a brief overview of breastcancer imaging will be performed. Next, the benefits and indications for PET/CT forbreast cancer patients will be discussed. Finally, case studies of the use of PET/CT inradiation treatment planning will follow.

BBrreeaasstt CCaanncceerr IImmaaggiinngg.. Mammography remains the mainstay of imaging for breastcancer screening. In patients with known breast cancer, it helps determine the extent ofdisease locally. This information in turn helps the clinician decide whether localtreatment by lumpectomy with radiation is adequate, or whether mastectomy isrequired. Ultrasound and breast MRI are complementary imaging modalities. Althoughtremendously important, all these modalities suffer from one main limitation: they onlylook at the breast itself, and can only discern structural anomalies. Because PET/CTimaging screens a much broader area of the body, and can often detect metabolicabnormalities before structural changes even occur, PET and PET/CT represent a greatcomplement to existing local imaging modalities. Although it cannot replace screeningmammography due to sensitivity and cost issues, PET/CT can be very helpfuldiagnostically for women with dense breasts or with abnormal axillary exams.

Before the era of PET/CT, our patients with locally advanced breast cancers wereinitially 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 lesssensitive than a bone scan, we currently stage these patients with PET/CT and bonescan. Our PET/CT scanner also performs F-18 bone scans. This approach not onlyallows “one stop-shopping” for the patient, but may well also result in cost savings overtime to the healthcare industry by reducing the number and variety of tests ordered.

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RRaaddiiaattiioonn PPoorrtt DDeessiiggnn:: tthhee IInnfflluueennccee ooff PPEETT//CCTT.. PET/CT is primarily used in theradiographic 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 axillarydissection are most likely to benefit from PET/CT staging. Nodal metastasis in thesupraclavicular, internal mammary, and mediastinal regions are more reliably identifiedby PET/CT than other imaging modalities including mammography, ultrasonography,MRI, and CT6. As noted above, mammography, ultrasonography, and MRI are all limitedby their field of view. These modalities and CT are also unable to identify metabolicallyactive cancerous tissue.

Defining the extent of nodal involvement is crucial for therapeutic decisions. Forradiation oncologists, it dictates the extent of the radiation fields. Obviously, if radiationfields do not adequately cover disease, the likelihood of local regional control issubstantially diminished. Case study #3 illustrates a recurrence at the margin ofstandard radiation fields of the chest wall. We now routinely use the PET/CT data tohelp design the extent of our radiation ports for both the chest wall and regional lymphnode areas.

Patients with breast cancer involvement of their lymph nodes are also more likely tohave distant metastasis. If distant metastasis is identified, therapeutic recommendationschange markedly. In some cases, the aggressiveness of local treatment may bereduced to allow greater emphasis on addressing disease at other sites. Therefore, asthe most sensitive, specific, and accurate method of identifying metastasis, the PET/CTscanning should be incorporated routinely into the staging procedure.

It should be noted, however, that PET/CT has limitations. Breast cancer is a spectrumof diseases. Some histological variants of breast cancer are more indolent than othersand take up FDG less avidly than more metabolically active tumors. Lobular breastcancer, for example, usually shows a lower uptake than invasive ductal carcinoma (7).Another PET/CT pitfall revolves around infection or inflammation: patients may haveabnormal uptake in normal breast tissue from inflammatory processes such asmastopathy or post-surgical healing. Despite these limitations, PET/CT is a useful toolfor staging and follow up of breast cancer patients.

Case Studies.CCaassee ##11.. Patient is a 45-year-old who presented with an almond-sized right axillarylump. Mammogram showed clustered pleomorphic calcifications associated withincreased density in the right upper outer quadrant. Several large lymph nodes, somewith pleomorphic calcifications, were also noted in the axilla and were consistent withmetastasis. Ultrasound revealed two masses in the right breast at 9:30 and 10:00measuring 2 and 2.5 cm. Three solid masses in the axilla measured up to three cm insize. Incisional biopsy of the breast lesions revealed invasive, poorly differentiatedductal carcinoma. Subsequent mastectomy and axillary node dissection confirmed athree cm invasive ductal carcinoma–grade 3 by the Modified Bloom Richardson system.

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Margins were free. Estrogen and progesterone receptors were negative, and Her2–neureceptors were positive. Four of 14 axillary lymph nodes were involved, with onemetastasis measuring greater than 2 cm, and another focus revealing microscopicextracapsular extension less than 2 mm from the nodal capsule. She was staged withCT 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 wasnegative. A PET scan was not performed. The medical oncologist decided to treat heras having non-metastatic disease, assuming the final stage was T2N2aM0. The planwas for serial chest CT scans for follow up. She received chemotherapy consisting ofAdriamycin, Cytoxan, Taxol, and Herceptin. Four-month follow-up chest CT revealedstability of the nodules, and the patient was referred to radiation oncology for treatmentrecommendations.

At this point a PET/CT scan was ordered. The indications were twofold. If the lungnodules were positive, suggesting uncontrolled metastatic disease, prophylactic chest-wall radiation would have been abandoned. With her extensive initial nodal involvement,we were also concerned about the possibility of extensive nodal involvement in thesupraclavicular, internal mammary, or mediastinal regions. The PET/CT scan wasperformed in the treatment position in a mold to allow its use in treatment portalplanning, should it have been positive in those expanded nodal areas. Fortunately, thePET/CT scan was negative in this case, and we proceeded with standard chest-walland nodal irradiation as shown in Figure 1:

FFiigguurree 11

CCaassee ##22.. An 83-year-old woman with severe COPD requiring 24-hour oxygen

51

supplementation presented with a large mass replacing the left breast and involving theskin. She had ignored the lesion for some time, and initially chose not to seek medicalattention. 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 co-morbidities. As the tumor was estrogen and progesterone receptor positive, she wasstarted on Tamoxifen. A PET/CT scan performed for staging and radiation treatmentplanning revealed a heterogeneously positive left breast mass involving overlyingdermal structures compatible with the patient’s malignancy. A 1-cm left axillary nodewas noted with low-grade FDG activity. It was felt to indicate early metastasisinvolvement of this lymph node. Clinically, supraclavicular adenopathy was noted, whichwas not seen on PET/CT. No definite evidence of distant metastasis was noted.

Based on the exam and scan this patient’s stage was T4aN3M0. Palliative radiation tothe breast and nodal regions was recommended to prevent further oozing, swelling, orbleeding of the mass. Radiation treatment planning incorporated the clinical andPET/CT scan findings. As noted in Figure 1, standard fields without the aid of scansmay have missed the axillary node seen on PET/CT scan. Figure 2 demonstrates howthe PET/CT scan findings help define the radiation fields. PET/CT was beneficial to thispatient by improving the quality of her radiation treatment and allowing comprehensivestaging with one test.

FFiigguurree 22..

CCaassee ##33.. This patient is a 42-year-old with bilateral breast cancer. Her stage was

52

T3N1M0 on the right and T4N2M0 on the left. A PET/CT scan was not included in herinitial staging. She underwent bilateral mastectomy and chemotherapy and was referredfor prophylactic bilateral chest wall radiation. Standard chest wall and supraclavicularfields were treated.

At her 3-month follow-up visit, new nodules on her left chest at the posterior axillaryline were noted. A PET/CT scan was obtained. The suspicious nodules werehypermetabolic, as was an AP window mediastinal lymph node (Figure 3).

FFiigguurree 33..

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

FFiigguurree 44..

CCoonncclluussiioonnss.. PET/CT scanning is a major new tool in the effort to successfully treatwomen with breast cancer. It provides more accurate staging of disease, which guidestherapeutic decisions. For radiation oncologists, treatment planning PET/CT scans willdiminish the rate of marginal misses in treatment of the breast, chest wall, and/orsurrounding nodal regions. For our patients, it provides a more convenient andcomprehensive 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 detectmediastinal 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 postoperativehistopathology, hormone receptor status, thymidine labeling index and p53 in primary breast cancer: a preliminaryobservation. Eur Nucl Med 1998:25:1429-1434.

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10. PET/CT in Gynecologic Radiation TherapyAbhijit Deshmukh, MD

Gynecologic cancers seen in radiation therapy practice include carcinomas of thecervix, uterus, vagina, and vulva. Radiation therapy plays an important role in themanagement of these cancers, either as definitive therapy or as adjuvant treatmentafter surgery. In addition, radiation therapy may have a role in ovarian cancer, althoughits use as part of the initial treatment strategy has fallen out of favor in comparison tochemotherapy. Gynecologic cancers are, in general, thought to begin as localizedlesions that may spread in an orderly progressive fashion to lymphatics and distantsites. Accurate staging is therefore of critical importance in radiation treatment planningfor gynecologic cancer. The more sensitive and specific the diagnostic informationavailable to the radiation oncologist, the better chance all sites of disease can beencompassed and effectively treated.

This chapter will present some cases seen in our practice in which PET/CT helped instaging, treatment planning, and follow-up. It is not intended as a comprehensivechapter but rather as an illustration of the benefit of using PET/CT in day-to-dayradiation oncology practice.

CCeerrvviiccaall CCaarrcciinnoommaa.. There were an estimated 10,520 cases of cervical cancer in theUnited States in 2004, and 3,900 deaths. Early-stage patients may be managed witheither surgery or radiation therapy, while locally advanced patients are usually treatedwith concurrent chemoradiotherapy. Important prognostic factors include FIGO stage,tumor volume, and pelvic or para-aortic adenopathy. Inoue retrospectively analyzed 875patients 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, orpara-aortic) also has prognostic importance, as reported by Terada.2 Indeed, the GOGreported that para-aortic adenopathy was the most significant prognostic factor amongpatients treated with radiation therapy.3

Staging of cervical cancer according to FIGO rules is based upon exam underanesthesia as well as allowed procedures including colposcopy, endocervical curettage,hysteroscopy, cystoscopy, proctoscopy, IVP, chest X-ray, and bone scan. Additionaltests 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 evaluationof lymph nodes. Grigsby reported on 101 consecutive patients who underwent bothPET and CT prior to standard radiation with chemotherapy if indicated.4 CTdemonstrated abnormally enlarged pelvic nodes in 20% and para-aortic nodes in 7% ofpatients. PET demonstrated abnormal FDG uptake in pelvic nodes in 67%, para-aorticnodes in 21%, and supraclavicular nodes in 8%. Two-year progression-free survival

55

based on para-aortic node status, was 64% in patients with negative CT and PET, butonly 18% with negative CT and positive PET. Patients with both CT and PET positivehad 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 whounderwent radical hysterectomy and pelvic lymphadenectomy. PET had highersensitivity and specificity than MRI, 91% versus 73% and 100% versus 83%respectively.

CCaassee ##11.. S.M., a 32-year-old female, presented with irregular vaginal bleeding andlower abdominal pain. Cervical biopsies confirmed squamous cell carcinoma. Examshowed stage T1b1 disease. Chest X-ray and CT of the abdomen and pelvis showedno evidence of metastasis. However, whole-body PET revealed a focus of activity in asmall 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.

FFiigguurree 11..

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 para-aortic node also confirmed metastatic carcinoma. Her treatment plan involved deliveryof 41 Gy to the upper para-aortic nodes, 46 Gy to the lower para-aortic nodes, and 50Gy to the pelvis, with concurrent cisplatin chemotherapy, followed by HDR intracavitarybrachytherapy to deliver an additional 30 Gy to point A in five sessions.

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CCaassee ##22.. S.C., a 41-year-old female, presented with a 4-month history of irregularvaginal bleeding and pelvic pain. Pap smear was suspicious for carcinoma. Examrevealed an 8-cm exophytic, fungating mass replacing the cervix, with extension andfixation to the left pelvic sidewall. Cervical biopsy confirmed invasive, poorlydifferentiated squamous cell carcinoma. She was clinically staged IIIB. CT of theabdomen and pelvis showed left hydronephrosis and hydroureter as well as an 8.1 x6.2 cm cervical mass, but no definite lymphadenopathy. However, PET showed twoFDG-avid, non-enlarged (<1.5 cm) nodes in the left internal iliac and right pelvicwall/obturator regions (Figures 2 and 3).

FFiigguurree 22..

FFiigguurree 33..

She received 45 Gy to the pelvis with IMRT boost to bilateral pelvic sidewalls to 54 to55 Gy with concurrent cisplatin chemotherapy. Follow-up PET/CT then showeddecreased FDG uptake in the cervical mass from initial SUV of 21.0 down to 10.9, inthe left iliac node from 5.0 to 2.1, and resolution of uptake in the right obturator nodefrom initial SUV of 11.0. She then received 30 Gy in five fractions to point A using HDRtandem and ring brachytherapy. Subsequent PET/CT two months post-brachytherapyshowed further decline in FDG uptake in the cervical mass from SUV of 10.9 to 5.2. NoFDG-avid pelvic or abdominal nodes were seen.

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VVaaggiinnaall CCaanncceerr.. There were an estimated 2,160 cases of vaginal cancer in the UnitedStates in 2004, and 790 deaths due to this disease. Vaginal cancer involving the upperthird of the vagina can spread to parametria and have lymphatic drainage similar tocervical 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 isbased on local invasion of tumor into parametrium or pelvic sidewall, and lymphatic ordistant metastases. FIGO stage is determined on the basis of exam under anesthesia,colposcopy (and Schiller test), chest X-ray, IVP, barium enema, cystoscopy, andproctoscopy. CT and MRI are also routinely used in evaluation. Search of the literaturedid not reveal published experience with PET in staging vaginal cancer, but it wasstrongly recommended as part of the standard evaluation for vaginal cancers, based onsimilarities with cervical cancer.5 The majority of patients with vaginal cancer aretreated primarily with radiation therapy, with the addition of concurrent cisplatin-basedchemotherapy in locally advanced cases.

CCaassee ##33.. H.W., a 67-year-old female, presented with a right groin mass, biopsy ofwhich showed metastatic squamous cell carcinoma. Staging work-up included negativeCT of the chest, abdomen, and pelvis; bone scan; and colonoscopy. On evaluation by agynecologic oncologist, she was noted to have a 1.5 x 1.5-cm raised, slightlyerythematous lesion just inside the anterior right introitus. Biopsy of this lesionconfirmed poorly differentiated, non-keratinizing squamous cell carcinoma, involvingsubmucosal tissues only. Subsequent PET scan showed a single, small, FDG-positivenode in the mid-abdominal pre-aortic region (Figure 4).

FFiigguurree 44..

She received 45 Gy to the pelvis and inguinal and para-aortic nodes, followed by 5.4Gy boost to the primary tumor in the distal vagina. She then received 18 Gy HDRintracavitary boost via vaginal cylinder. Interestingly, PET one month afterbrachytherapy 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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Bibliography1. 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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FFiigguurree 77..Short-term follow-up PETis pending.

FFiigguurree 66..Unfortunately, 4 monthsafter her negative PET, thesame node was found tobe hypermetabolic incomparison with liveractivity and wasconsidered to besuspicious (Figure 7).

FFiigguurree 55..Follow-up PET at 4 months wasessentially stable (SUV 6.2 versus 6.0previously). However, by 7 monthspost-treatment, the hypermetabolicnode had resolved (Figure 6).

1111.. LLyymmpphhoommaassTTiimmootthhyy JJaammiieessoonn,, MMDD,, BBrruuccee TTrriipppp,, MMDD

IInnttrroodduuccttiioonn.. In the United States, lymphoma–including Hodgkin’s disease (HD) andNon-Hodgkin’s Lymphoma (NHL)–is diagnosed in over 60,000 persons annually, andkills over 20,000. The incidence of NHL has increased steadily in the past 25 years. Thecure 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 beenimplemented. Significant factors in further reduction of toxicity and improvement insurvival will include better assessment of disease stage, localization, and response totreatment, enabling physicians to better tailor their treatment. PET/CT will likely play alarge role in that effort. We will briefly review the utility of PET in lymphomamanagement.

IInniittiiaall SSttaaggiinngg.. Staging of lymphoma requires a history and physical, laboratory data,bone marrow biopsy, and radiographic studies. PET has been shown in numerousstudies to be more accurate than CT in defining sites of disease.2,3 Stumpedemonstrated a PET sensitivity of 89% and specificity of 100% in NHL, and 86% and96%, respectively, for HD. In contrast, CT scans had a sensitivity of 86% and specificityof 67% for NHL, and 81% and 41%, respectively, for HD.4 Low-grade lymphomas hadbeen detected with lower sensitivity in older PET scanners, but new generation high-resolution equipment has overcome this limitation.2

PET has been shown to change the staging in 8% to 16% of NHL patients. 3% Up to41% of HD patients were upstaged in a recent study, as PET detected splenic andother extra nodal site involvement in about 20% of cases where CT was considerednegative.5 A dedicated dual modality PET/CT has been shown to be more accurate ininitial 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 uponhistopathology and clinical follow up.6 Determinations of lymphomatous involvement byCT are obviously based upon nodal size or anatomic data alone, and thecomplementary functional information from PET results in superior accuracy in definingsites of disease. CT will continue to be important in treatment planning as it has betteranatomic resolution than the corresponding PET.

RReessppoonnssee ttoo TTrreeaattmmeenntt.. PET is an excellent prognostic indicator at the completion offirst-line chemotherapy. The utility of CT scans alone in this setting is complicated bythe conundrum of residual masses that may be fibrosis or active tumor. PET can betterdetermine the viability of these masses. Spaepen performed PET before and after first-line chemotherapy in 93 patients with early stage NHL.7 Sixty-seven patients had anegative post-chemotherapy scan, and only 11 relapsed (median progression-free

60

survival 14 months), whereas all 26 patients with positive PET scans relapsed (medianprogression-free survival 2 months). Fourteen of these 26 patients had negative CTscans after first-line chemotherapy, and thus would have been incorrectly labeled ascomplete responders if a PET had not been performed.

Lavely reported that 21 NHL patients had negative PET scans after chemotherapyalone.8 Five relapsed in the site of initial disease. Twelve patients treated with combinedmodality had negative PET scans after chemotherapy, and none relapsed. The authorsconcluded that a negative PET scan thus does not preclude the presence ofmicroscopic disease, and thus radiation therapy should still be considered after acomplete radiographic response to chemotherapy in early-stage NHL. As small volumemicroscopic disease is not readily detected by PET, the initial sites of disease (ie, thepre-chemotherapy PET scan) should be carefully scrutinized in determiningconsolidative radiation fields.

Several investigators have shown the utility of PET before completion of first-linechemotherapy in predicting outcome.3 This utility might allow oncologists to switch fromineffective chemotherapy to alternative second-line chemotherapy or more aggressivealternatives such as bone marrow transplant earlier in the patient’s 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 onlyone or two cycles will be increasingly more important, so one can switch to a moreeffective regimen before excess toxicity is imparted and further time is wasted.

CCoonncclluussiioonnss.. PET/CT is an essential tool in the staging of lymphomas, its response totreatment, and in defining radiation fields. Its use in predicting response early duringthe first course of chemotherapy may ultimately improve outcomes in patients resistantto first-line chemotherapy. Though a negative PET scan after chemotherapy confers abetter prognosis than a positive PET, consolidative radiation therapy should still bestrongly considered in those with negative PET scans, as relapse in the site of initialdisease in this setting is not uncommon.

Bibliography.1. Jemal, A., et al: Cancer Statistics, 2004. CA Cancer J Clin 54:8-29, 20042. Kumar, R., et al: Utility of fluorodeoxyglucose-PET imaging in the management of patients with Hodgkin’s and non-

Hodgkin’s 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, 20044. 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 Hodgkin’s 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, 20018. Lavely, W., et al: FDG PET in the follow-up management of patients with newly diagnosed Hodgkin and Non-

Hodgkin Lymphoma after first-line chemotherapy. Int. J Radiation Oncology Biol. Phys. 57:307-315, 2003.

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12. BRAIN TUMORSMark Augspurger, MD

IInnttrroodduuccttiioonn.. The diagnosis of a primary or metastatic neoplasm within the centralnervous system (CNS) can present therapeutic challenges. Surgery may be necessaryto establish a diagnosis and/or alleviate acute mass effects. Due to the importance ofadjacent 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 diffusionacross the blood-brain barrier. Radiation therapy is not as constrained by theselimitations, and therefore has become entrenched as an essential treatment modality inthe management of both primary and metastatic brain neoplasms.

The scope of the brain tumor problem is substantial. The frequency of primary CNSmalignancies is directly associated with patient age with a total annual incidence of18,000 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 eachyear2.

Primary brain tumors can arise from a variety of tissues. The most common primarybrain tumors in adults are of glial origin. Unfortunately, over 50% of these adult glialtumors will be malignant (anaplastic glioma or glioblastoma multiforme). As these glialtumors comprise the bulk of the primary CNS tumors the radiation oncologist willencounter, the remainder of this chapter will refer to this subset of tumors whendiscussing primary brain tumors.

While radiation therapy has been proven effective, it is not without limitations. Theprimary obstacles in radiation delivery are normal tissue tolerance and tumor volumeidentification. Both issues complicate radiation treatment planning, and planning couldbe improved greatly if the physician could better differentiate between the target andnormal tissue.

BBrraaiinn TTuummoorr IImmaaggiinngg.. CT has been widely available to the radiation oncologist sincethe 1970s. This imaging provided the first in-vivo imaging of the neuroanatomy2. TheHoundsfield units of the CT image are directly related to the density of tissue, and ioniccontrast agents help detect the increased vascularity often seen with high-gradegliomas. Although the images are coarse, CT continues to play a role in both diagnosisand treatment planning for the radiation oncologist, due to its swift acquisition timesand 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 anatomicalimaging technique.

Functional imaging of the brain with Positron Emission Tomography (PET) has alsoproven to be useful in the evaluation of brain tumors. This capability has been presentsince the 1980s2. At that time, however, PET imaging was primarily limited to academicinstitutions and was considered mainly a research tool. Today, the widespreadavailability of PET scanning, has allowed the oncologist to use this modality in theclinical arena.

Perhaps one of the most important recent technological advances for the radiationoncologist has been the ability to fuse images from various diagnostic techniques3. MRIimages are optimal for imaging brain tumor anatomy. When now fused to the images ofa PET/CT, the radiation oncologist now has an unprecedented way to visualize thetumor 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 andedema, but also by metabolic tumor activity (Figure 1).

PPEETT IImmaaggiinngg ooff BBrraaiinn TTuummoorrss.. Generally, higher metabolic activity correlates withincreased 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 theprognosis of a patient with a glial brain tumor is highly dependent upon (and inverselyproportional to) the grade of the tumor, by inference the PET image intensity providesprognostic information to the oncologist.4,5 Although tumor grade also correlates withthe level of contrast enhancement seen on MRI, the FDG uptake on a PET scan hasbeen shown to be a more accurate predictor.2

Normal brain parenchyma has a significant glucose metabolism that unfortunatelyresults in a high degree of background uptake of FDG. This characteristic negativelyimpacts 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 auseful reference when evaluating primary brain tumors2. Due to their high rate ofproliferation and glycolysis, the malignant gliomas exhibit significant FDG uptake onPET imaging2. These tumors will have uptake similar to or greater than the adjacentbrain gray matter. Conversely, low-grade glial neoplasms usually have relatively lowerlevels 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 bereadily apparent on CT or MRI. PET/CT, however, can often discern differential uptakeacross a tumor. Indeed, at some institutions, PET imaging with MR fusion has beenincorporated into software for stereotactic biopsy guidance in an effort to reduce therisk 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 manymetastatic brain tumors can be identified on PET/CT imaging, the intense backgrounduptake of normal brain coupled with minimal tumor burden and the frequent location ofmetastasis at the gray-white junction, limits the usefulness of PET as a screening studyin asymptomatic patients. In our experience, PET/CT is most useful in evaluating brainmetastasis in symptomatic patients or in patients who have inconclusive readings ontheir MRI studies.

TTrreeaattmmeenntt PPllaannnniinngg ffoorr tthhee RRaaddiiaattiioonn OOnnccoollooggiisstt wwiitthh PPEETT//CCTT aanndd MMRR FFuussiioonn..TThhee SSiimmuullaattiioonn.. Patients are simulated and treated in the supine position. The patient’shead is placed in a neutral or flexed position, and at least four fiducial markers areplaced on the patient’s skin. Immobilization consists of an Aquaplastic™ maskextending from the vertex of the scalp to the shoulders and is attached to a MED-TECS-type™ headboard. The mask is removed and IV access is obtained. FDG isadministered 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 arerecorded in the PET/CT suite for patient set-up and shifts. The patient is then taken tothe MRI department and set up in a similar fashion. As the patient will not fit in the MRIbrain coil in this position, the full-body coil is used. T1with contrast and T2 axial imagesare obtained at the same 3 mm spacing as the CT. The PET/CT is then fused to theMR data set in the dosimetry department. Generally, the MRI to PET/CT fusion is within2 mm concordance.

TThhee PPllaann.. For a malignant glioma, we will treat the edema plus a 2 cm margin to 4500cGy. A boost will then be designed to treat the tumor plus 2.5-cm margin to a dosegreater than 6000 cGy (RTOG parameters). In contouring the initial volume, the T2 MRIdata set is primarily used as edema is well visualized. The PET/CT uptake is generallywell covered within this volume. If uptake is seen on the PET/CT extending beyond theedema, this is also given a 2-cm margin. The boost PTV (planning target volume) isdesigned utilizing the T1 contrast-enhanced data set as well as the PET/CT study. Allmonitored unit calculations are done on the CT data set.

RRaaddiioossuurrggeerryy.. PET/CT images can also be used to assist in the planning ofradiosurgical procedures. In this setting, the MRI data set obtained for radiosurgicalplanning is fused to the PET/CT images. Reports in the literature indicate that whenPET/CT has been incorporated, changes will be made to the MRI-based target volumein approximately 70% of cases7. PET imaging has also been helpful in assessing thetumor response to radiosurgery8. In our experience, PET/CT has been most beneficialin the radiosurgical planning of patients with recurrent gliomas. Figure 1 shows aPET/CT image of a patient who underwent gamma knife radiosurgery at our facilty.

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EEvvaalluuaattiioonn ooff RReessppoonnssee aanndd FFoollllooww--UUpp.. PET imaging can be an important tool in theevaluation and management of patients after they have completed a definitive course oftreatment. It is usually quite difficult to differentiate recurrent neoplasm from surgicaland radiation changes that occur within the brain parenchyma after treatment on MR orCT imaging. Surgical changes alone do not increase glycolitic metabolism andtherefore do not show increased FDG uptake on PET imaging2. Similarly, necrosis canoccur following radiation therapy and typically shows little uptake on PET imaging9.Overall, when PET is used to distinguish between necrosis and recurrent tumor, studieshave shown a sensitivity of 75% and specificity of 80%2. Unfortunately this iscomplicated by the fact that many patients have both tumor and necrosis present at thetime of progression. Nevertheless, at our institution we utilize both PET/CT and MRI forfollow-up of our patients with high-risk glial tumors. The following case illustrates thebenefit of this approach.

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FFiigguurree 11..The patient had previously had oneradiosurgical procedure and the PET/CT wasused to help differentiate the volume of activetumor progression from the previoustreatment changes.

CCaassee SSttuuddyy.. DG is a 51-year-old male who was found to have GBM of the righttemporal lobe in 2000. He underwent a gross total resection followed by adjuvantradiation 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 showedno change. A PET/CT was then performed that showed no uptake in the areas ofconcern on MRI. He was, however, noted to have a 1 cm area of abnormal uptake inthe right occipital lobe (Figure 3).

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 inthe occipital lobe with surrounding edema (Figure 4).

Again, no new abnormalities were noted around the prior operative site. The patientunderwent craniotomy the following day and was found to have a second glioblastoma

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FFiigguurree 22..

FFiigguurree 44..

FFiigguurree 33..

in the occipital lobe.FFuuttuurree AApppplliiccaattiioonnss.. Due to the relatively high background FDG uptake of normalbrain parenchyma, future PET imaging of brain tumors will likely be done with tracersother than FDG. Amino acid metabolism is higher in glial neoplasms than in normalbrain tissue. For example, C11-methionine has been studied and reveals good contrastbetween tumor tissues and normal brain10,11. Other radiolabeled amino acids are beingstudied as well. Lipid metabolism with F18-fluorocholine may prove to be a useful tracerfor brain tumor imaging11. Finally, O15 tracers have been used to study cerebral bloodflow2. This could be potentially useful to locate areas of functional criticality prior toradiosurgery. Wherever these exciting paths may lead, it is clear that PET/CT imagingwill 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 CANCERDwelvin Simmons, MD

Colorectal cancer is the third most common malignancy in the United States1. In 2004there 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 higherfor males in the rectum. The majority of these cases are adenocarcinomashistologically2.

The primary treatment of colorectal cancer is surgical resection. Cure rates areexcellent in patients with early-staged tumors. For more advanced tumors, there is amajor 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 theneoadjuvant or adjuvant setting. Preoperatively, it may downstage the tumor, making itmore surgically approachable, perhaps converting some patients to candidates forsphincter sparing procedures. Postoperatively, the role is to extirpate residual diseaseat the primary site, and nodal basins. When indicated, the survival advantages providedby chemotherapy and radiation are clear in rectal cancer.4,5,6

The clinical stage of colorectal cancer clearly impacts prognosis. Accurate staging ofthis disease can ensure that the most appropriate treatment be given. Along withcolonoscopy and biopsy, the radiographic evaluation of colorectal tumors is crucial. CTscans are useful for assessing invasion of neighboring structures as well as detectionof distant metastasis. Endorectal ultrasounds as well as endorectal MRI are veryaccurate in assessing depth of tumor invasion7.

FDG PET/CT is Medicare-approved for initial staging and follow-up of patients withcolorectal malignancies. In comparison to CT alone, PET/CT is more sensitive andaccurate for detection of tumor sites, especially with regard to regional lymph nodes8. Itis unusual for colorectal cancer to produce nodes larger than 1 cm, making it difficult toassess metastatic disease from reactive lymph nodes. Endorectal ultrasound andendorectal MRI also predict regional lymph nodes poorly9.

The design of conventional external beam treatment portals relies heavily upon thedetection of the extent of disease. This has involved the use of contrast-enhanced CTsimulation for 3D treatment planning. The field is designed to cover the primary site,presacral space, internal iliac, and distal common iliac nodes. Inguinal nodal coverageis necessary when tumor is within 2 cm of the anal verge. Fields typically include theperineum in postoperative cases. Typical preoperative radiation portals use a superiorborder 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 portalsencompass the entire sacrum posteriorly and should have coverage of the internal iliacnodes. There should be an adequate anterior margin upon the rectum. If dosing beyond45 Gy is necessary, these fields are appropriately reduced depending on the clinicalsituation. Some have even used smaller fields touting improved morbidity with similarresults.

IMRT has gained popularity given its ability to spare normal tissues and radiationinduced toxicity. There is a wide array of techniques used to accomplish IMRT10.

Ultimately, radiation given concurrently with chemotherapy in the preoperative orpostoperative setting is only effective if the disease is appropriately targeted. Ourpractice advocates the use of PET/CT in the simulation process to help better definethe target. Below are three cases in which the use of this imaging modality was crucialin defining treatment to all areas of disease:

CCaassee ##11.. A.B. is a 65-year-old man with a diagnosis of adenocarcinoma of the distalrectum with extension to the anal verge. The patient had experienced six months oftenesmus and bright red blood per rectum prior to colonoscopy. Biopsy returned thediagnosis. Of note, the remainder of the bowel had several polyps that were biopsiedand found to be benign. An outside CT demonstrated rectal wall thickening at theprimary site, but no evidence of metastasis or asynchronous primary. The patient wasreferred for preoperative radiation and chemotherapy prior to APR. He underwentPET/CT treatment planning with images shown (Figure 1).

FFiigguurree 11..

This study demonstrated readily the primary site. No lymph node metastasis or hepaticmetastasis was identified. However, there was an FDG avid cecal mass not seen at thetime of colonoscopy, consistent with a synchronous primary. This patient’s treatmentplan was changed to immediate right hemicolectomy and APR with postoperativetherapy to follow.

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CCaassee ##22.. C.L. is a patient with adenocarcinoma of the rectum (T3N1M0) with perianalskin involvement. This patient received an APR with seven of 21 nodes positive fordisease. Margins were positive at the perianal skin. Preoperative CT scandemonstrated no positive lymph nodes and no hepatic metastasis. Intraoperatively, theliver was felt to be free of disease. The patient was referred for postoperative radiationand chemotherapy. He underwent PET/CT simulation for treatment planning with theimages seen in Figure 2.

FFiigguurree 22..

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

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CCaassee ##33.. L.M. is a 72-year-old patient with adenocarcinoma of the rectum 8 cm abovethe anal verge, diagnosed after two months of bright red blood per rectum and decreasedstool caliber. The patient was referred for preoperative chemotherapy and radiation.Outside the CT showed no hepatic metastasis and no nodal involvement. The patientreceived PET/CT simulation for treatment planning. Her images are shown in Figure 3.

FFiigguurree 33..

Note the node at the distal common iliac chain. This very easily could have beengeographically missed using conventional radiation portals based upon conventional CTsimulation. Fields were designed to adequately cover the disease with appropriate margin.

Defining a target volume can vary to significant extent among observers, and anymodality limiting this variance should be welcomed. It is becoming clear that goodPET/CT imaging incorporated into the simulation process can improve radiationdelivery. This has been demonstrated for lung tumors in which a study showedapproximately 30% of patients had modification of their treatment portals due to PETimaging.11 Several studies have shown PET/CT to be extremely useful in the design ofradiation 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 specificthan CT scans. PET/CT has difficulty distinguishing inflammatory nodal disease fromactive tumor. Mucinous tumors accumulate less FDG, thereby decreasing the sensitivityof PET/CT in this type of colorectal tumor. At present, this modality is not widelyavailable, but this is rapidly changing.

It is our practice to routinely use PET/CT as part of the simulation process forcolorectal cancer. Data from PET and images is coregistered on an integrated PET/CTsystem, during one image acquisition session, limiting image fusion deviations. Ourpractice uses the CMS focal fusion software and a treatment plan is then derived usingXIO, CMS’s treatment planning system. Currently we are evaluating the fusion ofPET/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 high-

risk 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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1144.. CCOONNCCLLUUSSIIOONNShyam 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 willreplace the CT Simulator as the standard unit in all therapy departments. PET/CT hasutility in simulation and treatment planning of the following malignancies:

LLuunngg CCaanncceerrHHeeaadd && NNeecckk CCaanncceerrBBrreeaasstt CCaanncceerrCCeerrvviiccaall && UUtteerriinnee CCaanncceerrLLyymmpphhoommaassBBrraaiinn TTuummoorrssCCoolloorreeccttaall CCaanncceerrss

The list of malignancies suitable for PET/CT will only expand. We have developed apractical and useful method to cost-effectively utilize a Siemens Biograph PET/CT in amulti-clinic environment. By using centralized treatment planning and a network, we areable to provide this service for our patients. We are happy to share our experienceswith you. You may contact us at:

PPEETT//CCTT CCeenntteerr ooff NNoorrtthh FFlloorriiddaa1895 Kingsley Avenue, Suite 600Orange Park, FL 32073904-276-2338Larry Wilf, MD, Medical DirectorJohn Wells, Jr, MD, Clinical DirectorShyam Paryani, MD, Managing PartnerFaye 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 clinician’s judgment in how best to use any medical devices. It is the clinician who makes all diagnostic determinationsbased upon education, learning, and experience.

Note: Original images always lose a certain amount of detail when reproduced.

© 2006 Printed in USA06-18-PO-1362 10-2006