Three-dimensional Conformal Radiation Therapy

Bryant Furlow, B.A. Advances in computing hardware and software have made more precisely targeted radiation therapy possible. Three-dimensional conformal radiation therapy(3-D CRT) uses 3-D models to identify treatment plans that shape small radiation beams to a tumors contour. This article describes various aspects of 3-D CRT After reading the information presented, readers should be able to: List treatment and other volumes for three-dimensional conformal radiation therapy(3-D CRT) Describe patient immobilization for CRT. Explain the clinical benefits of 3-D CRT List techniques used to correct for respiratory movement during 3-D CRT imaging and treatment. Discuss the role of functional imaging techniques in CRT planning. Describe virtual simulations role technology. Explain the role of registration algorithms in integrating and automating planning processes. Describe the differences between 3-D CRT and intensity-modulated radiation therapy (IMRT)

Cancer is treated most successfully with radiation therapy or surgery before it has spread to distant organs. Although new chemotherapeutic and bioengineered approaches, such as engineered antibodies and gene therapy, show great potential for local tumor control, half of patients in the United States now receive radiation therapy during the course of their cancer treatment. Therapeutic radiation doses for localized solid tumors are determined not only by the dose required for tumor control but also by the radiosensitivity of non-target tissues. DNA-repair mechanisms of healthy cells tend to be significantly more effective than those in tumor cells, but radiation can kill healthy tissue or increase the long-term risk of secondary cancers. The higher ends of curative dose ranges often cannot be delivered in clinical practice because of toxicity to nontarget tissues within the irradiated volume. Radiation oncologists must balance the risk of 2 adverse outcomes: Treatment of too small a volume can fail to achieve tumor control and increase the probability of metastasis; however, irradiation of larger treatment volumes can damage healthy tissues and affect long-term survival.

Ideally, radiation therapy would precisely target only tumor tissues, completely avoiding irradiation of non-target tissue. Despite steady improvements, technological, physical and time limitations prevent perfect radiation therapy For example, calculating radiation beam angles with entry and exit pathways that avoid critical organs is not always possible. Until recently the problem was even more basic: Uniform beam shapes and intensities inevitably resulted in irradiation of healthy tissue within the target region. Even low-dose irradiation of healthy tissue can impair organ function. As advances in cancer treatment prolong patient survival, the longterm risk of secondary cancers is an increasingly important consideration in treatment planning. Three-dimensional Conformal Radiation Therapy Fine targeting of the radiation dose has become a more realistic goal with three-dimensional conformal radiation therapy (3-D CRT). Radiation delivery systems now are equipped with the advanced computing power and hardware necessary to precisely shape beams to contoured geometries. Simultaneous advances in radiation treatment planning systems permit detailed and highly accurate dose planning based on multi-modality imaging and pretreatment simulation. Three-dimensional CRT uses 2-dimensional image data from computed tomography (CT) scans, magnetic resonance (MR) imaging and other imaging modalities to build 3-D models. The resulting computer image can be rotated on screen and used to identify optimal beam angles and shapes. The final treatment plan consists of multiple small radiation beams that conform to the tumors contours while minimizing irradiation of nontarget tissues. Treatment usually is delivered by linear accelerator, and beams are shaped with a computer-controlled multileaf collimator. By shaping the radiation beam more closely to the tumor, 3-D CRT allows escalation of the therapeutic dose. An increasingly common treatment, it is particularly well suited for tumors surrounded by radiosensitive tissues. For example, conventional external-beam radiation therapy doses for prostate cancer are limited to approximately 65 Gy because of the prostates proximity to the rectum and bladder, whereas 3-D CRT permits safe dose escalation to 71 Gy.2 Men with intermediate-risk prostate tumors often receive conventional radiation therapy and brachytherapy because the radiation doses required for tumor control cannot safely be delivered by external-beam radiation alone. In a sense, brachytherapy is a conformal treatment because the radiation produced by the implants follows tumor contours: however, adjacent nontarget tissues still are irradiated. Recently, the consensus committee of the 3rd International Consultation on Prostate Cancer reported that although this combination therapy is still a viable therapeutic approach, 3-D CRTs lower morbidity ratesmake it the preferred treatment for intermediate-risk prostate cancer.5 Because of the tightly packed critical functional anatomy in the brain, 3-D CRT also is well suited for brain tumors.4 In clinical practice, however, alternative treatment techniques often are used instead (eg, gamma knife). Researchers and clinicians commonly refer to 3-D CRT as representing a new era in radiation therapy.5 To a degree not before possible, radiation therapy doses can be tailored to a patients anatomy and tumor, improving the probability of favorable outcomes. Further advances in conformal radiation therapy and planning, such as edge-detecting algorithms for contouring

tumor images, integrated analysis of imaging data from multiple modalities and intensitymodulated radiation therapy (IMRT) promise to achieve even greater therapeutic precision. Preplanning State-of-the-art 3-D CRT treatment planning involves 4 primary steps: defining the target volume and adjacent nontarget, radiosensitive tissues; simulating therapy; calculating the dose; and visualizing the dose distribution.6 Before these key steps are taken, however, clinicians must carefully preplan treatment. Three-dimensional CRT implementation hinges on how meticulously preplanning steps are executed. For example, preliminary imaging studies require precise immobilization so that treatment volumes and margins delineated during simulation can be reproduced accurately during treatment. As with conventional external-beam radiation therapy 4 volumes must be quantified: 1. Gross tumor volume (GTV). 2. Clinical target volume (CTV). This margin around the GTV represents the region of probable undetected microscopic tumor or primary tumor infiltration, 3. Planning target volume (PTV). This volume is a margin of error beyond the CTV to compensate fur CTV tissue movement out of the treatment volume due to setup errors or internal patient movement. CTV shape can shift due to slight changes in the patients body position, heart or lung motion, or the effects of ongoing radiation treatment. 4. Treated volume. This volume includes all target and nontarget tissues receiving radiation. Treatment volumes generally are calculated on a slice-by-slice basis by the radiation oncologist, although several automated margin delineation computer algorithms are in development.7 When the effects of radiation are likely to alter the target volumes between treatments, additional imaging of the treatment position may be necessary to identify changes and recalculate treatment volumes. Patient Immobilization The preplanning step most vulnerable to error is patient positioning. Setup accuracy varies significantly among institutions and radiation therapists.8 Even seemingly slight inconsistencies in patient positioning between fractions can compromise a carefully conceived treatment plan. Patient positioning for 3-D CRT is determined by the beam angles specified in a patients treatment plan and can deviate significantly from standard diagnostic imaging positions. After planning images are acquired, the radiation oncologist may find that the patients position does not allow the radiation beam to be delivered safely through healthy tissue. When this occurs, new patient positioning studies must be performed to verify that desired therapeutic beam angles are achieved. To ensure consistent, optimal dose delivery immobilization is necessary to maintain the

patients position during treatment. For each planned treatment position and tumor site, imaging studies of the immobilized patient must be performed to calculate the margins surrounding the CTV. Immobilization techniques and positioning used during treatment must exactly match the positions in which treatment volumes initially were calculated. The more effectively immobilized the patient, the more consistent and precise patient positioning will be from fraction to fraction. Precise, consistent patient positioning allows smaller treatment volumes to be delineated and, therefore, delivery of higher therapeutic radiation doses to target tissues. Even when the entire therapeutic dose is delivered during one session, patient position reproducibility is important because of the need to accurately track tumor response to treatment.9 Head-and-Neck immobilization When the total planned radiation dose is to be delivered in a single treatment session, invasive equipment is used to immobilize the head. Stereotactic frames are attached to the patient using up to 6 pins or screws that penetrate the skin to sit tightly against the outer surface of the skull. This often involves local anesthesia to reduce patient discomfort. Once in place, the stereotactic head frame is attached to a fixed base ring. Although they typically are not used for fractionated treatments, stereotactic head frames nevertheless exhibit excellent position reproducibility when used in fractionated treatment regimens.9 When the total dose is delivered over the course of more than one treatment session, customized masks typically are used instead of invasive fixation equipment. Masks are formed from quickdry cast bandages or polyurethane foam on a scaffolding of support brackets or steel plates that allow the device to be attached to a stereotactic frame. A neck roll or other neck support is incorporated into the mask. After the mask is formed, it is removed, and hin~s are attached so that it can be closed back over the patients face during treatment sessions. Studies show that these masks can reduce setup errors in patient positioning to less than 1 mm, allowing I to 2 mm PTV margins beyond CT Vs.0 Body Immobilization Effective body immobilization is considerably more difficult than head-and-neck immobilization. Target tissues can change position or shape between fractionated treatments, and rotational shifts around the long axis of the body can alter the position of internal organs. Face masks are sometimes used as part of a body immobilizing system to help control axial body position. Two common body immobilization techniques include quick-dry body casts and vacuum fixation. Body casts are made in a similar fashion as face masks. Quick-dry casts are wrapped around the patient while he or she is in the treatment position. After drying, the body cast is cut, equipped with hinges for easy refitting and fixed to a backboard attached to the stereotactic body frame. For vacuum fixation, the patient is positioned supine on an oversized vacuum bag or pillow that is partially filled with small beads. Side plates are strapped to the vacuum pillow on either side of the patient. The pillow then is evacuated, causing it to mold like heated shrink-wrap to the patients contours, and the plates are removed. The formfitting vacuum pillow now closely follows the back and sides of the patients body. A stereotactic frame is mounted over the

patient and attached to the sides of the pillow. If needed, an abdominal compression plate can be placed on the frame to reduce the patients range of breathing motion. The patient and pillow are marked with ink to note alignment.

Figure 1 Definition of the stereotactic frame of reference.

Stereotactic frames are integral to the use of casts and vacuum fixation equipment, and lightweight stereotactic frames have been designed for use with children.2 The frames can act as an objective set of coordinates for patient positioning using a Cartesian scheme. (See Fig. 1.) Fiducial markers, which are easily identified on radiographs and CT images, can be attached to the ring. The markers are used as reference points later for patient repositioning. Straight bar markers also can be placed on the stereotactic frame around the patients head as landmarks for treatment planning. CT imaging markers are steel or tungsten, while other suitable marker substances (eg, radioactive copper) are used for imaging modalities such as positron emission tomography (PET).

Immobilization Challenges Target organs vary in their vulnerability to setup error and positioning reproducibility.8 Each has unique immobilization problems. Particularly for treatment of tumors in the upper torso, patient respiration can be problematic.3 Immobilization challenges and techniques for specific target regions include: 1. Liver. Breathing motion can change liver position. Abdominal compression with a tri angular Perspex (thick plastic) plate attached to the stereotactic body frame reduces breathing artifacts during liver treatment. Prostate. Prostate movement caused by patient breathing is rarely an issue if patients are in the supine position,4 but when prostate immobilization is required, air-inflated rectal balloon catheters are an effective approach. Balloon catheters have the added benefit of displacing th3 radiosensitive tissues of the anterior rectal wall from treatment volumes, allowing reduced margin sizes. The degree of bladder filling also can change prostate shape and position between treatments. To standardize prostate position and shape, the patient can empty his bladder before each treatment and then drink a set volume of liquid. Breast. Standardizing the position of the breast relative to organs located beneath the ribcage is particularly difficult. Solutions include breast and chest casts that are made with the patients arm extended over her head. Lungs. Thoracic targets require relatively large margins because of the effects of breathing motion. Lung motion makes pulmonary tumors particularly difficult to target precisely Abdominal compression can significantly improve the reproducibility of con formal radiation therapy of lung tumors by reducing the range of breathing motion.6 Another technique for limiting lung motion is the use of jet ventilation, which inflates the lungs with high-pressure air. However, jet ventilation requires general anesthesia. Other alternatives to reduce lung motion-related imprecision include free-breathing respiratory gating or breathing synchronized radiation therapy7 Even when patients are immobilized, target tissue movement due to breathing or heartbeat can complicate treat ment. When breathing motion is a problem, one solution is to ask patients to hold their breath for short periods of time. If patients are not comfortable with breath holding, they can be coached to practice breath holds while in the treatment position.

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Gating Gating involves delivering radiation only during a specific phase of the breathing or heart beat cycle, when treatment volumes are in a designated position.13.8 One method of respiratory gating involves voltage signals from displacement detectors on the patient. When the detector signal indicates that the patient is in a preselected stage of the respiratory cycle, a gate pulse is conveyed to the linear accelerator, which then delivers the radiation beam until the voltage gate is closed. Imaging for Treatment Planning

Detailed imaging of tumor volumes and their often irregular edges plays a critical role in accurate CRT delivery To precisely define treatment volumes and margins, anatomical techniques such as CT and MR are used to image the immobilized patient. Sometimes functional imaging modalities, such as functional magnetic resonance (fMR) imaging, PET or single photon emission tomography (SPECT), are employed as well to add metabolic information concerning the extent of the tumor. Image registration software allows data acquired from multiple imaging modalities to be correlated for an information-rich planning model.9 This software is improved continually and is becoming increasingly sophisticated and automated. Nevertheless, it currently requires a considerable time investment by treatment planners. Computed Tomography CT is the workhorse of 3-D CRT planning. CT images are less prone to geographic distortions and provide relevant tissue density values to formulate precise treatment plans.2 There are several CT scanner designs, with third-generation, fan-shaped beam scanners currently the most common. X-ray tubes and detectors are mounted on a semicircular yoke or gantry that is rotated around the patient during image acquisition. Fourth-generation CT scanners employ a stationary circular array of detectors, and the x-ray tube rotates around the patient. Spiral CT scanners are even more advanced. Their slip ring design permits continuous scanning in one smooth gantry movement and acquires image data volumetrically rather than in 2-D slices. Spiral scanners also are faster than other CT technology, reducing motion artifacts by acquiring image during a single patient breath hold. Despite these advantages, however, spiral scanners are not as common as conventional scanners for 3-D CRT imaging. Slice thickness for CT tumor imaging typically is less than 4 mm, with no more than 4-mm spacing to ensure sufficient resolution and detail. The region surrounding the tumor can be imaged with thicker slices (eg, 8-mm slice thickness with 8-mm spacing).2 Advances in computing power for image reconstruction allow thinner (eg, 2 mm) spacing between acquired slices without slowing the imaging process. Thin-beam spacing Further improves image resolution in virtual reconstructed radiographs used for treatment planning. CT contrast agents are used to define tumor borders from surrounding, normal tissues. For headand-neck tumors, contrast media is administered~ intravenously; oral, rectal or IV contrasts are used to differentiate digestive and urinary tract tumors from surrounding anatomy CT image data are transferred to a computer that constructs the 3-D models of target volumes for tumor localization and volume delineation. Used alone, CT may have a significant limitation: research shows that CT-only planning can overestimate the CTV.22 However, multi-modality imaging is increasingly used for 3-D CRT planning and may soon replace CT-only planning. Magnetic Resonance Imaging MR uses powerful magnetic fields to image tissue densities. Protons within the atoms of cells have a microscopic magnetization due to their spin rate. Exposing millions of these particles to a

strong magnetic field causes a realignment of thee particles within that field. The magnitude of the magnetic shift is referred to as the flip angle. When the external magnetic field is removed, subatomic magnetization relaxes to its normal state, emitting energy as a radiofrequency pulse. MR often is superior to CT for demonstrating the boundaries between tumor and healthy tissues.6 This is particularly true for brain and prostate tumor delineation. MR data is not used alone for 3-D CRT planning, but typically is correlated with other imaging modalities, partly because of imaging distortions that are not always corrected by postacquisition computer algorithms. For example, fusing CT and MR images significantly improves the accuracy of prostate tumor localization and reduces the CTV, decreasing radiation exposure of radiosensitive rectal and bladder tissue by 5% to 10%. 22 Functional Imaging Tumors alter local tissue metabolism beFore gross morphological change is apparent; they also may microscopically infiltrate surrounding tissues. This is common in astrocytoma, neuroblastoma and glioblastoma brain tumors. Such small metabolic changes are not readily detected with anatomic (CT or MR) imaging. However, microscopic tumor tissue can be distinguished from healthy tissue using imaging modalities such as fMR and PET (See Fig. 2.) Accurately delineating the microscopic tumor boundary helps define treatment volumes that likely contain all tumor tissue, while minimizing radiation exposure of nontarget tissues. Therefore, functional imaging is increasingly included in 3-D CRT treatment planning.

Figure 2 Target definition using fused CT and PET images. The blue area on the right side of the image is a node highlighted by PET butundetected by CT.

PET and SPECT demonstrate 3-D metabolic changes using radioactive isotope-tagged tracers, and PET has become the gold standard in functional imaging for 3-D CRT planning. PET imaging not only can define tumor boundaries but also can show the most aggressively growing regions within a tumor. For example, radioactively labeled amino acids accumulate more quickly in regions where cells are replicating most rapidly For brain tumor imaging, standard MR offers little information not obtained by PET However, fMR is a useful alternative because changes in neuronal activity alter the microscopic magnetic properties of blood supplying those cells with oxygen. Differences in tumor and healthy brain

tissue metabolism therefore allow a very precise discrimination of tumor boundaries. The involvement of the motor cortex (the brain region involved in body movement) can be precisely mapped with fMR by having patients move body parts during scanning, providing invaluable information to determine safety margins around the tumor Treatment Volume Delineation After image data have been acquired, tumors are localized and nontarget organs are identified. This often is the most time-consuming step in the preplanning process. When multiple imaging modalities are used, target and nontarget structures must be outlined for each image series. Data from different imaging techniques are matched using registration algorithms. After the GTV is defined, the CTV and PTV are quantified. Depending on tumor shape and the extent of macroscopic and microscopic infiltration of surrounding tissues, GTV delineation can be a complex task. The CTV, which includes the GTV and a margin encompassing possible infiltration, also is difficult to define. Organs at Risk Organs at risk are tissues that are more radiosensitive than other healthy tissues. just as a PTV must be defined to account for potential positioning errors and deformation or movement of target volumes, a planning volume for organs at risk (the PRV) must be identified to spare those tissues. Healthy tissues with high contrast values compared with adjacent tissues car, be computer contoured using automated threshold extraction algorithms,24 but experienced radiation oncologists should check these and must still delineate healthy structures that have relatively low contrast values. Image Segmentation Delineation of target and relevant nontarget tissues is known as image segmentation. Threedimensional CRT segmentation is performed on a slice-by-slice basis. After image data are reviewed and appropriate slices are selected, the radiation oncologist typically quantifies the PTV, delineates organs at risk and outlines the patients body surface contours on sequential slices of a CT image series, while simultaneously viewing planar projection reference images. The GTV also is outlined to quantify tumor regression and treatment efficacy This often can be done with semi-automated segmentation algorithms based on edge detection or identification of anatomic regions with similar gray scale values. The computer-generated components of contour delineation then can be corrected after inspection. Proper segmentation of the CTV and PTV is more difficult than segmentation of body contours or the GTV because those volumes are not anatomic units. Rather they are conceptual volumes, defined by known characteristics of the tumor, organ motion data from patient positioning studies and the radiosensitivity of adjacent tissues.25 Manual segmentation of a given structure varies a great deal among experts, particularly conceptual volumes (ie, the CTV and PTV). There are several semiautomated segmentation algorithms available, each of which employs a different approach to identify contours and quantify treatment volumes. As semiautoniated and fully automated contouring algorithms

proliferate in coming years, volume delineation and treatment outcomes will become standardized. A recent study by Philippe Giraud and colleagues at the Curie Institute in Paris demonstrated the extent of variability in tumor volume definition. The study showed significant differences in even GTV volume delineation for non-small-cell lung cancer among and between radiologists and radiation oncologists at 5 French treatment centers.25 Radiologists and less-experienced clinicians of both specialties tended to delineate smaller volumes around tumors, the researchers found. Experienced clinicians were more likely to draw larger GTV boundaries.25 In fact, the same clinician may draw different contours on the exact same image slice at different times, perhaps reflecting the aspect of volume determination foremost in his or her mind at a given moment.52 Segmentation methods and algorithms vary from institution to institution, but regardless of which technique is used, it is important that segmentation for a given imaging study and imaging studies fur a given patient always use the same approach because results from different approaches or algorithms may not be comparable. To date, no analysis has been published that compares the relative accuracy and precision of contouring algorithms. Not surprisingly, segmentation errors can serio1tsly compromise treatment efficacy and accurate interpretation of tumor responses to treatment. Segmentation quality depends on an array of factors, including imaging and acquisition parameters, image data processing algorithms, display quality of the computer monitor and the contouring expertise of the clinician. Generally speaking, the smaller or more poorly contrasted an organ or tumor, the less accurately it can be contoured during segmentation. Registration Each imaging technique provides unique data on aspects of the tumor and surrounding anatomy Therefore, images from multiple modalities often are fused to create single images that contain the maximum information for planning. (See Fig. 3.) This requires converting all image data into a single visual currency that ensures pixels of a given anatomy or volume match one another Aligning anatomic landmarks is one approach to registration. Matching multiple pairs of coordinate pixel points within different image sequences is another23 After the coordinates for landmarks or point pairs are calculated for each image sequence, a transformation matrix or conversion algorithm can be applied that correlates data from one image sequence with corresponding data in other sequences.23 Yet another approach is surface matching, in which an entire surface contour is matched rather than single pixel points or anatomical landmarks. This approach uses millions of point matches rather than just a few and ensures that single-point errors do not have large effects on overall data correlation.23 The registration methods described above use data from within the patient. Often, a more accurate way to integrate data from different image sequences is to use objective, external landmarks on immobilization devices and skin, or marks on stereotactic frames.28 Such

landmarks are called artificial because they coordinate different data sets of imaged anatomy by means of points that are not part of that anatomy.

Figure 3 PET/CT fusion imaging. A. CT coronal, PET coronal and fused coronal image. B. CT transaxial, PET transaxial and fused transaxial image.

After data from different image series are registered, they can be displayed using image fusion algorithms.23 Because fused hybrid images contain information from all imaging modalities used, they can be more accurate and precise than their constituent parts.22 Alternatives to image fusion include checkerboard integration of images acquired with different modalities23 or the sliding window technique. With a sliding window display, a primary image slice is shown on screen, and by moving a cursor over different regions of the primary image, the user can overlay the secondary image.

Figure 4. 3-D volume rendering of a lung cancer patient.

Registration methods are applied to other aspects of 3-D CRT as well. For example, the need for very precise delivery of escalated doses to inoperable lung tumors has led to the development of a fluoroscopy/CT coregistration program. CT imaging alone cannot safely account for complex lung tumor movement due to patient breathing, but registration of CT and fluoroscopy images can accurately model tumor movement and, therefore, calculation of the necessary margins. This is an important advance regardless of whether respiratory gating is used. Registration will play an increasingly important role in the integration of 3-D CRT planning processes. Planning Volumetric Patient Models Clinicians use volumetric models to study the effects of different beam configurations on physical dose distributions so that the most effective approach can be chosen. A 3-D model of the patients anatomy, tumor and treatment volumes is constructed from individually segmented 2-0 image slices. This model then can be used to test and customize beam shapes and angles and alternative treatment strategies. In addition, the body contour slices can be manipulated using triangulation and rendering algorithms to generate a translucent model of the bodys surface, within which relevant anatomy and treatment volumes are visible. (See Fig. 4.)

Virtual Simulation Conventional radiation therapy treatment planning is routine for radiation oncology clinics. Blocking and patient positioning procedures are practiced in a real-world setting, often using the radiation source as an imaging device to confirm planned beam angles. Virtual treatment planning uses a computerized simulation environment, ~ith imaging data taking the place of the actual patient. The virtual patient is a 3-D model created from different volume and surface renderings and virtual radiographs. During simulation, the virtual patient appears on the computer display complete with treatment volumes and organs at risk. Virtual controls match the real ones used in treatment. Because planning is performed digitally at computer workstations, it is possible for experts who are geographically distant to collaborate via the Internet when necessary5 Special collaborative simulation programs have been designed for this purpose. Although traditional treatment planning can be performed in conjunction with virtual simulation, particularly to detect setup errors and calibrate the planning process,34 virtual simulation for 3-D CRT will become standard practice in coming ears. Three-dimensional CRT virtual simulation carries out the planned treatment on the patient model, allowing corrections and adjustments in beam shapes and beam directions before treatment is undertaken. initial beam placement is either chosen arbitrarily or by a predetermined arrangement, such as the standard 6-field prostate plan.2 After the treatment planner chooses a beam direction, it should be checked using beams eye views (BEV5) to confirm that the target volume is completely enclosed by the beam, while taking into consideration the organs at risk.35 The goal is to select multiple beam angles that allow small individual beams to deliver the therapeutic dose to the tumor and minimize radiation to nontarget tissues along the beam entry and exit paths. The shapes of selected beam angles can be tailored to tumor contours using BEV simulations. During treatment, computer-controlled multileaf collimators (MLCs) attached to the radiation source shape the beam. When an initial beam placement plan is formulated, prescription dose weights are assigned to each beam. Isodose distributions are calculated with this information, and dosimetry outcomes are presented onscreen, typically as a 3-D transparent cage surface rendering and as a planar contour in a navigable set of sagittal, horizontal and coronal reconstructions. Planar views are used in addition to the cage surface representation because renderings for underlying volumes can be obscured by the isodose cage. Planar views allow treatment planners to double-check volume and isodose relationships when they are unclear in the surface model. Graphical displays of dose-volume histograms are also typically available on-screen. The simulated observers view is used to ensure that the net isometric dose space the volume in which the beam isocenters intersect or overlap is as small as possible while still enveloping the CTV. (See Fig. 5.) Virtual simulation can help avoid overlooked or unanticipated problems with treatment plans and optimize beam configurations. BEV displays assist in optimizing beam shapes and angles,

Figure 5. A. Beam's eye view. B. Observer's view.

but these displays often do not show that a given beam ~ direction will be obstructed by a table or gantry during treatment. Simulations therefore also employ room-view displays that detect such extrinsic limitations to beam configuration and the treatment plan. Digitally Reconstructed Radiographs X-ray images called digitally reconstructed radiographs (DRRs) also are used in treatment planning. Ray-tracing algorithms generate the images, using tissue density data embedded in the 3-D patient model. Because arbitrary view angles are digitally reconstructed from the patients CT image series, DRRs can be created in any orientation. In ray tracing, a view angle is selected, and virtual beams or rays pass through the volume at the selected angle. The algorithm identifies the CT values (represented as pixel or voxel brightness) encountered along each rays path and encodes each paths summed value for representation in the final image. The summedvalue data is assembled into a DRR. Dose calculation is based on ray tracing as well because it can be used to calculate radiation absorption of tissues along any beam angle. At the time of treatment, DRR5 can be used to confirm proper patient positioning. Electronic portal imaging devices (EPID5) image patients positioned for treatment from the perspective of the radiation source (a real-world BEV). Automated registration algorithms the cocorrelate these images in real-time with DRRs used in treatment planning to detect any significant setup errors.36 Because this process is very fast, it is likely to be used for online collaborations in the future. DRRs usually are derived from CT imaging, but magnetic resonance DRRs are also in use and have proven reliable in assuring accurate patient positioning for monitoring brain tumors posttreatment.37

Dose Calculation Dose calculation is a critical step in treatment planning. The goal of 3-0 CRT is to maximize radiation dose to tumors while minimizing irradiation of nontarget volumes; dose calculation for a given treatment plan reveals to what extent this goal is achieved. Dose calculations can be represented graphically as components of the patient model and as dose-volume histograms. Graphical representations of dose distribution allow the radiation oncologist to evaluate a treatment plan and identify and correct problems. Pencil Beam Method For dose calculation purposes, the electron beam can be modeled as a collection of singleelectron beams, each referred to as a pencil beam. Dose distributions are calculated for each pencil beam within a planned beam and then summed to determine a given beams dose. The degree of electron side scattering (pencil beam expansion) also is estimated. However, the pencil beam method assumes that radiation beams pass through homogeneous-density anatomy, which is often not the case with 3-D CRT Monte Carlo Method The Monte Carlo method is a more biologically realistic and accurate technique for dose calculation when volumes contain tissue density heterogeneities. The technique models the transport of radioactive particles within each beam through the specified tissue densities identified from the patient model. Probabilities are calculated for beam attenuation and irradiation along the proposed beam path, taking into consideration stochastic particle behaviors. By repeatedly running simulations, net or average beam/biology interaction outcomes can be calculated. However, these simulations can be very time consuming up to 100 times longer than the time required for the pencil beam technique.38 Monte Carlo methods are therefore not currently in widespread clinical use. However, faster computer processors or wider use of parallel processing networks in radiation therapy departments may lead to the adoption of this dose calculation method. Dose-volume Histogram Planned radiation doses for 3-D volumes can be very complex. Therefore, doses for each contoured volume in a treatment plan are graphically summarized as dose-volume histograms (DVH5). DVHs can be used to detect whether part of a volume will receive more radiation than intended under the treatment plan being analyzed. DVHs also are used to help the clinician assess the risks of nontarget tissue complications.390 Generally, though, patient models and DVHs currently show radiation dose delivery without explicitly modeling the likely biological effects of those dose distributions. Because much is known about the biological responses of different tissue types to radiation, automated calculation of the probable biological effects of a given treatment plan, such as tumor control probability (TCP)4 and normal tissue complications probability (NTCP), may be incorporated into radiation therapy planning computer programs in the future. Optimization

The goal of optimization is to identify the best possible treatment plan. Essentially, the clinician repeats virtual simulation, dose calculation and evaluation of calculated doses, refining the treatment plan as needed. The number of adjustments and trips through the optimization loop42 varies from patient to patient, tumor to tumor and from physician to physician. Even when an optimal treatment plan theoretically exists, it is unlikely that this best possible plan will be identified. The initial beam direction is chosen arbitrarily, and this starting point determines what final plans are possible. Indeed, optimization might be considered more akin to refined treatment planning. Some authors have suggested that optimization be called plan configuration.42 Physical Simulation After a treatment plan is formulated with the aid of virtual simulation, it still may be necessary to perform a physical simulation before the first day of treatment. Patient images are acquired from the perspectives of planned beam angles so that DRRs can be created to verify the viability of the treatment plan. Far more often, however, less time consuming and expensive positioning verification systems (eg, EPID5) are used on the first day of treatment. Treatment Treatment begins when a final, optimized treatent plan is selected. Linear accelerators are the most common equipment used for 3-D CRT delivery, with proton accelerators used less frequently Multileaf Collimators Conventional beam collimators, which are composed of 2 pairs of collimating jaws oriented at right angles to one another, produce rectangular-shaped beams of various sizes. First developed and patented in the 1 980s, MLC5 represent a major improvement over conventional collimators. They are now the state-of-the-art method for shaping radiation beams to match the contours of target volumes and customizing radiation dose delivery Several generations of MLCs have been developed but all are composed of banks of independently positioned leaves. The leaves are made of tungsten to minimize undesired radiation transmission. Fine-resolution micro-MLCs are employed for small fields (approximately 10 x 10 cm2).43 Larger fields (up to 40 x 40 cm2) use standard MLC5. MLCs are computer-controlled, with a resolution of between 0.5 and 2.0 cm. MLCs have played a key role in the development of 3-D radiation therapy. Special long-leaf MLCs make it possible to adjust beam intensity rather than just changing the shape of a uniform-intensity beam, so that beam intensity is greatest where tumor thickness or growth is greatest.

Patient Positioning For 3-D CRT treatment, it is critical that patient positioning exactly match the positioning shown in planning images. The patient initially is positioned and immobilized using the techniques and devices employed during image acquisition. Skin marks or marks on immobilization casts help approximate ~ the proper position; stereotactic coordinates and digital portal imaging then are used to precisely match positioning. (See Fig. 6.) In practice, precise realignment can be difficult even with the aid of positioning-assistance technologies. Stereotactic Positioning To precisely align the patients target volume isocenter with the isocenter in the treatment plan, a stereotactic positioning device composed of targeting slide plates is mounted to the stereotactic base ring. The plates have cross hairs that are placed at predetermined reference points derived from the treatment plan. The immobilized patient is moved beneath the positioning device until its cross hairs match the laser light lines indicating the accelerator beam isocenter

Portal Imaging Portal imaging shows a BEV of the patient positioned for treatment. Traditionally, portal images are compared with the planning images. Because this is time consuming, comparisons are made after fractionated treatment, and adjustments are made for the subsequent treatment. This method does not avoid targeting errors during the initial treatment session in which the portal image is acquired. Digital or electronic portal imaging that uses fluoroscopy or ionization chamber arrays is a superior approach. EPIDs allow real-time comparisons of digital portal images and planning images to verify and correct target volume position before treatment begins.36 The use of registration-like algorithms for comparing images will become routine clinical practice, allowing automated assessment of positioning. Quality Assurance Regular inspection and verification of the linear accelerator and other equipment are integral to reliable 3-D CRT. Quality assurance (QA) involves periodic constancy tests in which baseline consistency is confirmed, and tests should be undertaken to check accelerator and MLC calibration and functioning before each patient is treated. Institutional QA protocol should be followed meticulously to maintain equipment precision and integrity Clinical Outcomes Three-dimensional CRT is a young treatment technique: clinical outcomes are only beginning to be reported in sizeable numbers in the medical literature. No major prospective clinical trial with control groups has been completed for most applications of this treatment approach. Nevertheless, preliminary clinical reports and several randomized studies of 3-D CRT for prostate cancer are optimistic concerning its role in cancer treatment. Researchers at the University of Michigan, where 3-D CRT to treat prostate cancer was pioneered, and at M.D. Anderson Cancer Center in Houston, have found that, in addition to tumor control, 3-D CRT reduces toxicity compared with conventional external-beam radiation therapy44~48 There are, however, problems associated with 3-D CRT For example, irradiation of radiosensitive oontarget tissue during 3-D CRT of prostate cancer is a potential problem in highdose treatments (eg, 73.8 Gy), with possible sexual and quality-of-life impairment for the patient. Precise delivery of radiation to pulmonary GTVs is particularly challenging. One recent retrospective study5 conducted in the Netherlands indicated that 3-D CRT failed to control lung tumors in substantial numbers of patients. Patients included in the study were treated as long ago as 1991 when 3-D CRT first was implemented. Methodology and tools have advanced since then. However, given inconsistency among clinicians in delineating the GTV in this form of lung cancer,25 it is possible that the theoretical benefits of 3-D CRT for lung cancer treatment are being lost in clinical practice. More studies comparing outcomes for conventional radiation therapy vs 3-D CRT of lung cancer clearly are needed.

One study of 1 9 patients with nonsmall-cell lung cancer conducted at M.D. Anderson Cancer Center indicated that 3-D CRT caused radiation pneumonitis (7 patients) and radiation-induced fibrosis (all 19 patients), though the study did not directly compare the extent or incidence of these problems in 3-D CRT vs traditional radiation therapy.5 A separate study reported by Sang Sim and colleagues at Memorial Sloan-Kettering Cancer Center in New York indicated that 3-D CRT interacts synergistically with preradiatioo systemic chemotherapy in cases of locally advanced nonsmall-cell lung cancer, suggesting that technical difficulties with pulmonary 3-D CRT could be partially compensated for with multi-modality treatment strategies.52 3-D CRT and IMRT 1lntensity-modulated radiation therapy (IMRT) is like 3-D CRT in that the radiation beam conforms to the tumors contours. However, IMRT also varies the intensity of the radiation beam across the treatment field. Preliminary studies suggest that IMRT offers improved control of nontarget tissue irradiation and toxicity for several cancer types, and it is widely believed that clinicians will come to prefer IMRT technology over 3-D CRT approaches.5354 Problems with IMRT dose heterogeneity and a lack of data on the basic radiobiological effects and long-term clinical consequences of IMRT time-dose-fraction schedules leave some authors cautious about the techniques eventual role in cancer treatment.55 It also should be noted that there is a lack of long-term outcome data for 3-0 CRT as well. Both are young technologies. Because IMRT still is largely under development, there likely will be a long transition period during v4iich IMRT and 3-D CRT will be used side by side. When the 2 approaches provide equivalent therapeutic benefits (eg, for early-stage prostate cancer), other factors such as planning time, expense and even the risk of secondary, radiation-induced cancers will guide the choice of radiation therapy technique for a given patient.56 A potential advantage of 3-D CRT over IMRT is a lower risk of some types of secondary cancers. For reasons that remain poorly understood, radiation therapy patients suffer an increased risk of secondary carcinomas in tissues receiving relatively low doses of irradiation and an increased risk of developing sarcoma-type cancers in tissues within the treatment volumes receiving the highest radiation doses.57 Some evidence suggests that the linear relationship between radiation dose and the risk of secondary cancers plateaus or even dkcreases at higher radiation doses.57 IMRT and 3-D CRT high-dose treatment delivery are similar, making it unlikely that the risk of secondary sarcomas will differ much between these techniques. However, IMRT dose distributions appear more likely to result in secondary carcinomas because patients often are exposed to more fields, and greater amounts of normal tissue are exposed to low-dose radiation. Multileaf collimators also allow more radiation leakage than is seen with conventional collimators, further increasing levels of unintended IMRT low-dose irradiation compared with 3-D CRT.5758 Among patients surviving a decade after radiation therapy authors estimate that IMRT will nearly double the incidence of secondary cancers compared with conventional radiation

therapy5759 When long-term patient survival is likely and IMRT and 3-D CRT provide equivalent tumor control, secondary cancer risk may become an important issue. Conclusion With 3-D CRT, the long-standing therapeutic goal of delivering the maximum radiation dose to target tissues while minimizing exposure to nontarget tissues is becoming a reality Practical and technological challenges remain, and economic cost/benefit analyses of 3-D CRT have not yet been reported. However, advances on several fronts promise to bring truly conformal radiation therapy into routine clinical practice in the coming years. A strong trend toward automating planning processes and image registration, for example, may lead to completely integrated and seamless treatment planning within the decade. Such automation will revolutionize the laborintensive approaches currently in use.2 Image compression and rapid image calculations will allow long-distance 3-D CRT clinical collaborations over the Internet. Large prospective clinical trials have yet to confirm the benefits of 3-D CRT and IMRT across a wide range of tumor types. In the future, however, it seems reasonable that radiation oncologists will routinely decide between 3-D CRT and 1MRT rather than conventional, nonconformal radiation therapy techniques. References 1. Davidson SE, Symonds RP, Snee MP, et al. Assessment of factors influencing the outcome of radiotherapy for bladder cancen Brj Urol$ 1990;66:288-293. Fukanaga-Johnson N. Results of 3D conformal radiotherapy in the treatment of localized prostate cancer. IntJ Radiat Oncol Biol Phys. 1997:38:311-317. Carlson RH. 3D conformal radiotherapy is safer than a brachytherapy-external beam combination. Lancet Oncol. 2002;3:51 9. Weil MD. Conformal radiotherapy for brain tumors. 1-Jematol Oncol Clin N Am. 2001:15:1007-1050. PurdyjA. 3-D radiation treatment planning. Front Radiat Ther Oncol. 1 996:29:1-1 6. Schlegal W. Basics of fields of application. In: Schlegel W, Mahr A. 3D Conformal Radiation Therapy: Multimedia Introduction to Methods and Techniques. Heidelberg, Germany: Springer Electronic Media; 2001:8-Il. McKenzie A, van Herk M, Mijoheer B. Margins for geometric uncertainty around organs at risk in radiotherapy Radiother Oncol. 2002:62:299-307. Hurkmans CW, Remeijer P, Lebesque jV, et al. Set-up verification using portal imaging: review of current clinical practice. Radiother Oncol. 2001:58:105-120. Salter BJ, Fuss M, Vollmer DG, et al. The TALON removable head frame system for stereotactic radiosurgery/radiotherapy: measurement of the repositioning accuracy Jnt] Radiat Oocol Biol Phys. 2001:51:555-562. Karger CP, Jakel 0, Debusj, eta!. Three-dimensional accuracy and interfractional reproducibiiity of patient fixation and positioning using a stereotactic head mask system. Int J Radiat Oncol Biot Phys. 2001:49:1493-1504. Ebert M, Pfeiffer K. Patient immobilization. In: Schlegel W, Mahr A. 3D Conformal

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Copyright 2003 All right reserved. ASRT newsletter The Journal of Radiation Oncology Sciences Radiation Therapist Fall 2003, Vol 12, No 2